Aryl sulfonamides and sulfamide derivatives and uses thereof

ABSTRACT

This invention is directed to novel aryl sulfonamide and sulfamide compounds which bind selectively to and inhibit the activity of the human Y5 receptor. This invention is also related to uses of these compounds for the treatment of feeding disorders such as obesity, anorexia nervosa, bulimia nervosa, and abnormal conditions such as sexual/reproductive disorders, depression, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure or sleep disturbances and for the treatment of any disease in which antagonism of a Y5 receptor may be useful.

This application is a continuation of PCT International application No.PCT/US96/19085, filed Nov. 27, 1996, designating the United States ofAmerica and a continuation of U.S. Ser. No. 08/566,104, filed Dec. 1,1995 now abandoned.

Throughout this application, various references are referred to withinparentheses. Disclosures of these publications in their entireties arehereby incorporated by reference into this application to more fullydescribe the state of the art to which this invention pertains. Fullbibliographic citation for these references may be found at the end ofthis application, preceding the sequence listing and the claims.

BACKGROUND OF THE INVENTION

The peptide neurotransmitter neuropeptide Y (NPY) is a 36 amino acidmember of the pancreatic polypeptide family with widespread distributionthroughout the mammalian nervous system (Dumont et al., 1992). Thefamily includes the namesake pancreatic polypeptide (PP), synthesizedprimarily by endocrine cells in the pancreas; peptide YY (PYY),synthesized primarily by endocrine cells in the gut; and NPY,synthesized primarily in neurons (Michel, 1991; Dumont et al., 1992;Wahlestedt and Reis, 1993). All pancreatic polypeptide family membersshare a compact structure involving a “PP-fold” and a conservedC-terminal hexapeptide ending in Tyr³⁶ (or Y³⁶ in the single lettercode). The striking conservation of Y³⁶ has prompted the reference tothe pancreatic polypeptides' receptors as “Y-type” receptors (Wahlestedtet al., 1987), all of which are proposed to function as seventransmembrane-spanning G protein-coupled receptors (Dumont et al.,1992).

NPY and its relatives elicit a broad range of physiological effectsthrough activation of at least five G protein-coupled receptor subtypesknown as Y1, Y2, Y3, Y4 (or PP), and the “atypical Y1”. While the Y1,Y2, Y3, and Y4 (or PP) receptors were each described previously in bothradioligand binding and functional assays, the “atypical Y1” receptor isunique in that its classification is based solely on feeding behaviorinduced by various peptides including NPY.

The role of NPY in normal and abnormal eating behavior, and the abilityto interfere with NPY-dependent pathways as a means to appetite andweight control, are areas of great interest in pharmacological andpharmaceutical research (Sahu and Kalra, 1993; Dryden et al., 1994). NPYis considered to be the most powerful stimulant of feeding behavior yetdescribed (Clark et al., 1984; Levine and Morley, 1984; Stanley andLeibowitz, 1984). The stimulation of feeding behavior by NPY is thoughtto occur primarily through activation of the hypothalamic “atypical Y1”receptor. For example, direct injection of NPY into the hypothalamus ofsatiated rats can increase food intake up to 10-fold over a 4-hourperiod (Stanley et al., 1992). Similar studies using other peptides hasresulted in a pharmacologic profile for the “atypical Y1” receptoraccording to the rank order of potencies of peptides in stimulatingfeeding behavior as follows: NPY₂₋₃₆≧NPY˜PYY˜[Leu³¹,Pro³⁴]NPY>NPY₁₃₋₃₆(Kalra et al., 1991; Stanley et al., 1992). The profile is similar tothat of a Y1-like receptor except for the anomalous ability of NPY₂₋₃₆to stimulate food intake with potency equivalent or better than that ofNPY. A subsequent report in J. Med. Chem. by Balasubramaniam andco-workers (1994) showed that feeding can be regulated by [D-Trp³²]NPY.While this peptide was presented as an NPY antagonist, the publisheddata at least in part support a stimulatory effect of [D-Trp³²]NPY onfeeding. In contrast to other NPY receptor subtypes, the “feeding”receptor has never been characterized for peptide binding affinity inradioligand binding assays. The fact that a single receptor could beresponsible for the feeding response has been impossible to validate inthe absence of an isolated receptor protein; the possibility exists, forexample, that the feeding response could be a composite profile of Y1and Y2 subtypes.

This problem has been addressed by cloning rat and human cDNAs whichencode a single receptor protein, referred to herein as Y5, whosepharmacologic profile links it to the “atypical Y1” receptor. Theidentification and characterization by applicants of a single molecularentity which explains the “atypical Y1” receptor allows the design ofselective drugs which modulate feeding behavior. It is important tonote, though, that any credible means of studying or modifyingNPY-dependent feeding behavior must necessarily be highly selective, asNPY interacts with multiple receptor subtypes, as noted above (Dumont etal., 1992).

As used in this invention, the term “antagonist” refers to a compoundwhich decreases the activity of a receptor. In the case of a G-proteincoupled receptor, activation may be measured using any appropriatesecond messenger system which is coupled to the receptor in a cell ortissue in which the receptor is expressed. Some specific but by no meanslimiting examples of well-known second messenger systems are adenylatecyclase, intracellular calcium mobilization, ion channel activation,guanylate cyclase, and inositol phospholipid hydrolysis. Conversely, theterm “agonist” refers to a compound which increases the activity of areceptor.

In order to test compounds for selective binding to the human Y5receptor the cloned cDNAs encoding both the human and rat Y2 and Y4 (orPP) receptors have been used. The human and rat Y5 receptors weredisclosed in PCT International Application No. PCT/US95/15646, publishedJun. 6, 1996, and filed as a continuation in part of U.S. Ser. No.08/349,025, filed Dec. 2, 1994, the contents of which are herebyincorporated by reference into this application. The human and rat Y2receptors were disclosed in PCT International Application US95/01469,published Aug. 10, 1995, as WO 95/21245, and filed as acontinuation-in-part of U.S. Ser. No. 08/192,288, filed Feb. 3, 1994,the contents of which are hereby incorporated by reference into thisapplication. The human and rat Y4 receptors were disclosed in PCTInternational Application PCT/US94/14436, published Jul. 6, 1995, as WO95/17906, and filed as a continuation-in-part of U.S. Ser. No.08/176,412, filed Dec. 28, 1993, the contents of which are herebyincorporated by reference into this application. The Y1 receptor hasbeen cloned from a variety of species including human, rat and mouse(Larhammar et al, 1992; Herzog et al, 1992; Eva et al, 1990; Eva et al,1992).

The synthesis of novel aryl sulfonamide and sulfamide compounds aredisclosed which bind selectively to the cloned human Y5 receptorcompared to the other cloned human NPY receptors, and inhibit theactivation of the cloned human Y5 receptor as measured in in vitroassays. The in vitro receptor binding and activation assays describedhereinafter were performed using various cultured cell lines, eachtransfected with and expressing only a single Y-type receptor. Inaddition, the compounds of the present invention were shown to inhibitin animals either NPY-induced feeding behavior or feeding behaviorexhibited by food-deprived animals.

This invention is also directed to the treatment of feeding disorderssuch as obesity and bulimia nervosa using the compounds describedherein. In addition, the compounds of the present invention may also beused to treat abnormal conditions such as sexual/reproductive disorders,depression, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure or sleep disturbances, or any condition inwhich antagonism of a Y5 receptor may be useful.

SUMMARY OF THE INVENTION

This invention is directed to novel aryl sulfonamide and sulfamidecompounds which bind selectively to and inhibit the activity of thehuman Y5 receptor. This invention is also related to uses of thesecompounds for the treatment of feeding disorders such as obesity,anorexia nervosa, bulimia nervosa, and abnormal conditions such assexual/reproductive disorders, depression, epileptic seizure,hypertension, cerebral hemorrhage, congestive heart failure or sleepdisturbances and for the treatment of any disease in which antagonism ofa Y5 receptor may be useful.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having the structures:

wherein Ar is

wherein each Z is independently N or C;

wherein each Y is independently N or C;

wherein p is an integer from 0 to 2;

wherein o is an integer from 0 to 1 and a is an integer from 0 to 3;

wherein V is S, O, N, or NR₅;

wherein X is a single bond or —NH—;

wherein each R₂ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₂-C₄ alkenyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl;C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂;NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; SO₂N(R₅)₂;phenoxy; phenyl; pyridyl; thiophenyl; naphthyl; phthalimide; C₅-C₇lactam, C₅-C₇ cyclic imide, C₅-C₇ cyclic amino; wherein the phthalimide,lactam, cyclic imide, or cyclic amine is linked by nitrogen; and whereinthe phenoxy, phenyl, pyridyl, thiophenyl, naphthyl, phthalimide, lactam,cyclic imide, or cyclic amine is substituted with H, F, Cl, Br, I, CF₃,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, or NO₂;

wherein each R₃ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₂-C₄ alkenyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl;C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂;NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; SO₂N(R₅)₂; or R₂and R₃ present on adjacent carbon atoms can constitute C₅-C₇ cycloalkyl,C₅-C₇ heterocycloalkyl or C₅-C₇ heteroaryl;

wherein each R₄ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; or SO₂N(R₅)₂; P1 whereineach R₅ is independently H; C₁-C₃ alkyl; C₁-C₃ monohaloalkyl; or C₁-C₃polyhaloalkyl;

wherein L′ is —NR₁—L— or

wherein L is C₃-C₉ alkyl; C₃-C₉ alkenyl; C₃-C₉ alkynyl;

 or

wherein R₁ is H; or C₁-C₃ straight chained alkyl;

wherein the alkyl, alkenyl or alkynyl is substituted with H, OR₅, CN,C₁-C₆ alkyl, CH₂OR₅, CON(R₅)₂, CO₂R₅, phenyl, pyridyl, thiophenyl ornaphthyl;

wherein one dashed line is a double bond and the other dashed line is asingle bond;

wherein each R₆ is independently H; CN; OR₅; C₁-C₅ alkyl; CH₂OR₅;CON(R₅)₂; CO₂R₅; phenyl; pyridyl; thiophenyl or naphthyl; wherein thephenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl,Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, or NO₂;

wherein i is an integer from 1 to 4; wherein n is an integer from 0 to3; wherein m is an integer from 0 to 3;

wherein K is —CH₂—NR₁₀—CHR₇—(CH₂)_(j)—; —CH₂—NR₁₀—CO—(CH₂)_(j)—;—CH₂—NH—CO—NH—(CH₂)_(j)—; —CO—NH—CHR₇—(CH₂)_(j)—;—CH₂—NR₁₀—CO—CHR₇—(CH₂)_(j); —CH₂—NR₁₀—CS—(CH₂)_(j)—;—CH₂—NH—CS—NH—(CH₂)_(i)—; —CS—NH—CHR₇—(CH₂)_(j)—;—CH₂—NR₁₀—CS—CHR₇—(CH₂)_(j); or —CH₂—N═CSR₁—NH—(CH₂)_(j);

wherein j is an integer from 0 to 3;

wherein R₇ is H; C₁-C₆ alkyl; CH₂OR₅; —(CH₂)_(p)NHCO₂R₅;(CH₂)_(p)NHSO₂R₅; CH₂N(R₁₁)₂; phenyl; pyridyl; thiophenyl; or naphthyl;

wherein W is

wherein Q is O; S; N; NR₉; or C(R₅)₂;

wherein b is an integer from 1 to 2;

wherein R₈ is independently H; F; Cl; Br; I; NO₂; OH; ═O; C₁-C₄ alkyl;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; or SO₂N(R₅)₂;

wherein R₉ is H; C₁-C₃ alkyl; COR₅; CO₂R₅; CON(R₅)₂;

wherein R₁₀ is H; or C₁-C₆ alkyl;

wherein R₁₁ is H; COR₅; COR₁₂; SO₂R₅; SO₂R₁₂; and

wherein R₁₂ is phenoxy; phenyl, pyridyl; thiophenyl; or naphthyl;wherein the phenoxy, phenyl, pyridyl, thiophenyl or naphthyl issubstituted with H, F, Cl, Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, NO₂, phenyl, pyridyl or thiophenyl; or a pharmaceuticallyacceptable salt thereof.

The invention also provides for the (+) and (−) enantiomers to thecompounds described herein.

In one embodiment the invention provides for a compound as describedabove, where R₁ is H;

where L is selected from C₃-C₉ alkyl or

where the alkyl is substituted with H, OR₅, CN, C₁-C₆ alkyl, CH₂OR₅,CON(R₅)₂, CO₂R₅, phenyl, pyridyl, thiophenyl or naphthyl; and

where W is

In other embodiments of the present invention, the compounds may havethe structures where Ar is selected from:

where each of R₂, R₃ and R₄ is independently H; F, Cl, Br or I; NO₂; OH;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ monohaloalkyl; C₁-C₄polyhaloalkyl; or N(R₅)₂; where X is a single bond; where each R₅ isindependently C₁-C₃ alkyl;

where L is selected from C₅-alkyl or C₇-alkyl; or

where R₇ is H; CH₂OH; or CH₂OR₅;

where W is

and where R₉ is H; or C₁-C₃ alkyl.

In other embodiments of the present invention Ar is selected from:

and K is —CH₂—NR₁₀—CHR₇—(CH₂)_(j)—.

Additional embodiments of the present invention include the compoundsselected from the group consisting of:

or

 or

Additional embodiments of the present invention include those in which Lis C₅-alkyl or C₇-alkyl.

In an embodiment of the invention the compounds have the structure:

In one embodiment of the invention K is —CH₂—NR₁₀—CO—(CH₂)_(j)—.

In another embodiment of the invention the compound has the structure:

In yet another embodiment of the present invention K is—CH₂—NH—CO—NH—(CH₂)_(j)—.

In a further embodiment of the invention the compound has the structure:

The invention also provides for a method of modifying feeding behaviorof a subject which comprises administering to the subject an amount of acompound effective to decrease the consumption of food by the subject soas to thereby modify feeding behavior of the subject, where the compoundhas the structure:

wherein Ar is

wherein each Z is independently N or C;

wherein each Y is independently N or C;

wherein p is an integer from 0 to 2;

wherein o is an integer from 0 to 1 and a is an integer from 0 to 3;

wherein V is S, O, N, or NR₅;

wherein X is a single bond or —NH—;

wherein each R₂ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₂-C₄ alkenyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl;C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂;NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; SO₂N (R₅)₂;phenoxy; phenyl; pyridyl; thiophenyl; naphthyl; phthalimide; C₅-C₇lactam, C₅-C₇ cyclic imide, C₅-C₇ cyclic amino; wherein the phthalimide,lactam, cyclic imide, or cyclic amine is linked by nitrogen; and whereinthe phenoxy, phenyl, pyridyl, thiophenyl, naphthyl, phthalimide, lactam,cyclic imide, or cyclic amine is substituted with H, F, Cl, Br, I, CF₃,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, or NO₂;

wherein each R₃ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₂-C₄ alkenyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl;C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂;NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; SO₂N(R₅)₂; or R₂and R₃ present on adjacent carbon atoms can constitute C₅-C₇ cycloalkyl,C₅-C₇ heterocycloalkyl or C₅-C₇ heteroaryl;

wherein each R₄ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; or SO₂N(R₅)₂;

wherein each R₅ is independently H; C₁-C₃ alkyl; C₁-C₃ monohaloalkyl; orC₁-C₃ polyhaloalkyl;

wherein L′ is —NR₁—L— or

wherein L is C₃-C₉ alkyl; C₃-C₉ alkenyl; C₃-C₉ alkynyl;

wherein R₁ is H; or C₁-C₃ straight chained alkyl;

wherein the alkyl, alkenyl or alkynyl is substituted with H, OR₅, CN,C₁-C₆ alkyl, CH₂OR₅, CON(R₅)₂, CO₂R₅, phenyl, pyridyl, thiophenyl ornaphthyl;

wherein one dashed line is a double bond and the other dashed line is asingle bond;

wherein each R₆ is independently H; CN; OR₅; C₁-C₅ alkyl; CH₂OR₅;CON(R₅)₂; CO₂R₅; phenyl; pyridyl; thiophenyl or naphthyl; wherein thephenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl,Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, or NO₂;

wherein i is an integer from 1 to 4; wherein n is an integer from 0 to3; wherein m is an integer from 0 to 3;

wherein K is —CH₂—NR₁₀—CHR₇—(CH₂)_(j)—; —CH₂—NR₁₀—CO—(CH₂)_(j)—;—CH₂—NH—CO—NH—(CH₂)_(j)—; —CO—NH—CHR₇—(CH₂)_(j)—;—CH₂—NR₁₀—CO—CHR₇—(CH₂)_(j); —CH₂—NR₁₀—CS—(CH₂)_(j)—;—CH₂—NH—CS—NH—(CH₂)_(i)—; —CS—NH—CHR₇—(CH₂)_(j)—;—CH₂—NR₁₀—CS—CHR₇—(CH₂)_(j); or —CH₂—N═CSR₁—NH—(CH₂)_(j);

wherein j is an integer from 0 to 3;

wherein R₇ is H; C₁-C₆ alkyl; CH₂OR₅; (CH₂)_(p)NHCO₂R₅; (CH₂)_(p)NHSO₂R₅; CH₂N (R₁₁)₂; phenyl; pyridyl; thiophenyl; or naphthyl;

wherein W is

wherein Q is O; S; N; NR₉; or C(R₅)₂;

wherein b is an integer from 1 to 2;

wherein R₈ is independently H; F; Cl; Br; I; NO₂; OH; ═O; C₁-C₄ alkyl;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; or SO₂N(R₅)₂;

wherein R₉ is H; C₁-C₃ alkyl; COR₅; CO₂R₅; CON(R₅)₂;

wherein R₁₀ is H; or C₁-C₆ alkyl;

wherein R₁₁ is H; COR₅; COR₁₂; SO₂R₅; SO₂R₁₂; and

wherein R₁₂ is phenoxy; phenyl, pyridyl; thiophenyl; or naphthyl;wherein the phenoxy, phenyl, pyridyl, thiophenyl or naphthyl issubstituted with H, F, Cl, Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, NO₂, phenyl, pyridyl or thiophenyl; or a pharmaceuticallyacceptable salt thereof.

In one embodiment of the method described above the subject is avertebrate, a mammal, a human or a canine. In another embodiment thecompound is administered in combination with food.

The invention also provides for a method of modifying feeding behaviorwhere the compound has the structure:

The invention further provides a method of treating a feeding disorderin a subject which comprises administering to the subject an amount of acompound effective to decrease consumption of food by the subject, wherethe compound has the structure:

wherein Ar is

wherein each Z is independently N or C;

wherein each Y is independently N or C;

wherein p is an integer from 0 to 2;

wherein o is an integer from 0 to 1 and a is an integer from 0 to 3;

wherein V is S, O, N, or NR₅;

wherein X is a single bond or —NH—;

wherein each R₂ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₂-C₄ alkenyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl;C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂;NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; SO₂N(R₅)₂;phenoxy; phenyl; pyridyl; thiophenyl; naphthyl; phthalimide; C₅-C₇lactam, C₅-C₇ cyclic imide, C₅-C₇ cyclic amino; wherein the phthalimide,lactam, cyclic imide, or cyclic amine is linked by nitrogen; and whereinthe phenoxy, phenyl, pyridyl, thiophenyl, naphthyl, phthalimide, lactam,cyclic imide, or cyclic amine is substituted with H, F, Cl, Br, I, CF₃,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, or NO₂;

wherein each R₃ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₂-C₄ alkenyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl;C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂;NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; SO₂N(R₅)₂; or R₂and R₃ present on adjacent carbon atoms can constitute C₅-C₇ cycloalkyl,C₅-C₇ heterocycloalkyl or C₅-C₇ heteroaryl;

wherein each R₄ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; or SO₂N(R₅)₂;

wherein each R₅ is independently H; C₁-C₃ alkyl; C₁-C₃ monohaloalkyl; orC₁-C₃ polyhaloalkyl;

wherein L′ is —NR₁—L— or

wherein L is C₃-C₉ alkyl; C₃-C₉ alkenyl; C₃-C₉ alkynyl;

wherein R₁ is H; or C₁-C₃ straight chained alkyl;

wherein the alkyl, alkenyl or alkynyl is substituted with H, OR₅, CN,C₁-C₆ alkyl, CH₂OR₅, CON(R₅)₂, CO₂R₅, phenyl, pyridyl, thiophenyl ornaphthyl;

wherein one dashed line is a double bond and the other dashed line is asingle bond;

wherein each R₆ is independently H; CN; OR₅; C₁-C₅ alkyl; CH₂OR₅;CON(R₅)₂; CO₂R₅; phenyl; pyridyl; thiophenyl or naphthyl; wherein thephenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl,Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, or NO₂;

wherein i is an integer from 1 to 4; wherein n is an integer from 0 to3; wherein m is an integer from 0 to 3;

wherein K is —CH₂—NR₁₀—CHR₇—(CH₂)_(j)—; —CH₂—NR₁₀—CO—(CH₂)_(j)—;—CH₂—NH—CO—NH—(CH₂)_(j)—; —CO—NH—CHR₇—(CH₂)_(j)—;—CH₂—NR₁₀—CO—CHR₇—(CH₂)_(j); —CH₂—NR₁₀—CS—(CH₂)_(j)—;—CH₂—NH—CS—NH—(CH₂)_(i)—; —CS—NH—CHR₇—(CH₂)_(j)—; or—CH₂—NR₁₀—CS—CHR₇—(CH₂)_(j); or —CH₂—N═CSR₁—NH—(CH₂)_(j ;)

wherein j is an integer from 0 to 3;

wherein R₇ is H; C₁-C₆ alkyl; CH₂OR₅; (CH₂)_(p)NHCO₂R₅;(CH₂)_(p)NHSO₂R₅; CH₂N(R₁₁)₂; phenyl; pyridyl; thiophenyl; or naphthyl;

wherein W is

wherein Q is O; S; N; NR₉; or C(R₅)₂;

wherein b is an integer from 1 to 2;

wherein R₈ is independently H; F; Cl; Br; I; NO₂; OH; ═O; C₁-C₄ alkyl;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; or SO₂N(R₅)₂;

wherein R₉ is H; C₁-C₃ alkyl; COR₅; CO₂R₅; CON(R₅)₂;

wherein R₁₀ is H; or C₁-C₆ alkyl;

wherein R₁₁ is H; COR₅; COR₁₂; SO₂R₅; SO₂R₁₂; and

wherein R₁₂ is phenoxy; phenyl, pyridyl; thiophenyl; or naphthyl;wherein the phenoxy, phenyl, pyridyl, thiophenyl or naphthyl issubstituted with H, F, Cl, Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, NO₂, phenyl, pyridyl or thiophenyl; or a pharmaceuticallyacceptable salt thereof.

In an embodiment of the present invention the feeding disorder may beobesity or bulimia. In another embodiment of the present invention thesubject is a vertebrate, a mammal, a human or a canine. The inventionalso provides for the decrease in the consumption of food by the subjectby the compound inhibiting the activity of the subject's Y5 receptor.

The invention further provides a method of treating a feeding disorderin a subject which comprises administering to the subject an amount ofone of the following compounds:

This invention also provides a method for treating a disorder in asubject which is alleviated by administering to the subject an amount ofa compound described herein which is a Y5 receptor antagonist.

This invention additionally provides a method of treating obesity in asubject which comprises administering to the subject an amount of a Y5receptor antagonist compound described herein.

This invention additionally provides a method of treating non-feedingdisorders in a subject which comprises administering to the subject anamount of a compound described herein which is a Y5 receptor antagonist.

This invention further provides that any of the methods for treating maycomprise administering to the subject a plurality of compounds describedherein.

The invention also provides for the (−) and (+) enantiomers of thecompounds of the subject application described herein. Included in thisinvention are pharmaceutically acceptable salts and complexes of all ofthe compounds described herein. The salts include but are not limited tothe acids and bases listed herein. The following inorganic acids;hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid,sulfuric acid and boric acid. The organic acids; acetic acid,trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid,glycolic acid, lactic acid and mandelic acid. The following inorganicbases; ammonia, hydroxyethylamine and hydrazine. The following organicbases; methylamine, ethylamine, propylamine, dimethylamine,diethylamine, trimethylamine, triethylamine, ethylenediamine,hydroxyethylamine, morpholine, piperazine and guanidine. This inventionfurther provides for the hydrates and polymorphs of all of the compoundsdescribed herein.

This invention further provides for the metabolites and precursors ofthe compounds of the present invention. The in vivo actions of numerousenzymes responsible for the generation of metabolites of pharmaceuticalcompounds are well-known in the art. For example, ethers may be modifiedto alcohols, or esters may be modified by esterases to yield acids asproducts. Knowledge of the activities of endogenous enzymes also allowsthe design of precursors or prodrugs of the compounds of the presentinvention, which when administered to a subject, such as a vertebrate ora human, are expected to yield metabolites which include the compoundsof the present invention. For example, secondary amines may be modifiedby various substituents, such as methyl, alkanoyl, aroyl, or alkyl oraryl carbamates may be formed, which are expected to yield the compoundsof the present invention when acted upon in vivo by endogenous enzymes.Such modifications are intended only as illustrative examples, and arenot intended to limit the scope of the present invention, as suchmodifications and techniques therefor are well-known in the art.

The invention also provides a pharmaceutical composition comprising atherapeutically effective amount of the compounds described above and apharmaceutically acceptable carrier. In the subject invention a“therapeutically effective amount” is any amount of a compound which,when administered to a subject suffering from a disease against whichthe compounds are effective, causes reduction, remission, or regressionof the disease. In one embodiment the therapeutically effective amountis an amount from about 0.01 mg per subject per day to about 500 mg persubject per day, preferably from about 0.1 mg per subject per day toabout 60 mg per subject per day and most preferably from about 1 mg persubject per day to about 20 mg per subject per day. In the practice ofthis invention the “pharmaceutically acceptable carrier” is anyphysiological carrier known to those of ordinary skill in the art usefulin formulating pharmaceutical compositions.

In another embodiment the pharmaceutical carrier may be a liquid and thepharmaceutical composition would be in the form of a solution. In yetanother embodiment, the pharmaceutically acceptable carrier is a solidand the composition is in the form of a powder or tablet. In a furtherembodiment, the pharmaceutical carrier is a gel and the composition isin the form of a suppository or cream. In a further embodiment thecompound may be formulated as a part of a pharmaceutically acceptabletransdermal patch.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Sterileliquid carriers can also be utilized for intranasal administration, forexample with the use of a pressurized composition, or for inhalatoryadministration. The liquid carrier for pressurized compositions can behalogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Carriers are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings.

The compound can be administered orally in the form of a sterilesolution or suspension containing other solutes or suspending agents,for example, enough saline or glucose to make the solution isotonic,bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleateesters of sorbitol and its anhydrides copolymerized with ethylene oxide)and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration includesolid forms, such as pills, capsules, granules, tablets, and powders,and liquid forms, such as solutions, syrups, elixirs, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

One skilled in the art will readily appreciate that appropriatebiological assays will be used to determine the therapeutic potential ofthe claimed compounds for treating the above noted disorders.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

EXPERIMENTAL DETAILS Synthetic Methods

The compounds of the present invention may be synthesized according tothe methods described in Schemes 1-4, as described herein. It isgenerally preferred that the respective product of each process step, asdescribed hereinbelow, is separated and/or isolated prior to its use asstarting material for subsequent steps. Separation and isolation can beeffect by any suitable purification procedure such as, for example,evaporation, crystallization, column chromatography, thin layerchromatography, distillation, etc. While preferred reactants have beenidentified herein, it is further contemplated that the present inventionwould include chemical equivalents to each reactant specificallyenumerated in this disclosure.

Temperatures are given in degrees Centigrade (° C.). The structure offinal products, intermediates and starting materials is confirmed bystandard analytical methods, e.g., microanalysis and spectroscopiccharacteristics (e.g. MS, IR, NMR). Unless otherwise specified,chromatography is carried out using silica gel. Flash chromatographyrefers to medium pressure column chromatography according to Still etal., J. Org. Chem. 43, 2921 (1978).

Synthesis of Compounds According to Scheme 1

Preparation of the compounds of the present invention having thestructure shown in Formula 1-2, Scheme 1, was carried out usingwell-known methodology for the preparation of a sulfonamide or sulfamidefrom an amine. Preferably the appropriate arylsulfonyl or arylsulfamoylhalide, preferably the chloride (i.e., Ar—X—SO₂Cl), is reacted with amonoprotected linear or cyclic alkylamine (Krapcho and Kuell, Synth.Comm. 20(16):2559-2564, 1990) comprising H₂N—L—K″, where K″ comprisesmethylene, in the presence of a base such as a tertiary amine, e.g.,triethylamine, dimethylaminopyridine, pyridine or the like, in anappropriate solvent (e.g. CHCl₃, CH₂Cl₂) as shown in Scheme 1, step A,followed by deprotection of the resulting amine as shown in Scheme 1,Step B, all under mild conditions (typically room temperature), to yieldthe deprotected amine of Formula 1-1. Alternatively, the primary amineH₂N—L may be replaced with a secondary amine wherein L comprises apiperidine. The arylsulfonyl or arylsulfamoyl halides are either knownin the art or can be prepared according to methods well known in theart.

The deprotected amine may be converted to the product amine of Formula1-2 by either a single step or two step reductive amination with an arylsubstituted aldehyde W—CHO as shown in Scheme 1, Step C, in the presenceof a solvent such as toluene or dioxane, at elevated temperature,followed by reduction using sodium borohydride in a solvent such asethanol. The K″ amine and the aldehyde carbon attached to W togetherform K in the product.

Compounds of Formula 1-3 in Scheme 1, wherein R₁ is H and j=0 and Kcomprises an amide, may be synthesized from the compound of Formula 1-1by amidation using suitable methods such as those taught in “ThePeptides,” Vol. 1 (Gross and Meinehofer, Eds. Acaemic Press, N.Y.,1979). For example, the compound of Formula 1-1 may be treated with acarboxylic acid derivative of W in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) anddimethylaminopyridine (DMAP) in a suitable solvent such as CH₂Cl₂ asshown in Scheme 1, Step D, at room temperature in an inert atmosphere ofargon or nitrogen, to yield the amide compound of Formula 1-3. As in theprevious method, the K″ amine and the carboxylic acid carbon attached toW together form K in the product.

Alternatively, the compound of Formula 1-3 may be synthesized byacylation of the amine of Formula 1-1 using the acid chloride of W,i.e., WCOCl or W(CH₂)_(j)COCl where j is an integer from 1 to 3, in asolvent such as CH₂Cl₂ and a suitable tertiary amine such astriethylamine, at room temperature. Again, the K″ amine and the acidchloride carbon attached to W together form K in the product.

This method also provides an alternative path to the compounds ofFormula 1-2 by reduction of the amide of Formula 1-3 usingborane-tetrahydorfuran (THF) complex, in THF as shown in Scheme 1, StepE, at elevated temperature in an inert atmosphere.

Compounds of Formula 1-4 in Scheme 1 where K comprises a ureido moietymay be synthesized by urea formation between the the compound of Formula1-1 and a substituted aryl isocyanate or aryl carbamate, as shown inScheme 1, Step F, in a suitable solvent and a suitable tertiary aminesuch as triethylamine and N-methylmorpholine, at room temperature in aninert atmosphere. The ureido moiety comprising K is formed between theK″ amine and the isocyanate (or isothiocyanate) attached to W, orbetween K″ and the carbamate derivative of W. Alternatively, compoundscontaining a thiourea moiety instead of a urea moiety may be synthesizedsimilarly by simply replacing the aryl isocyanate described above withan aryl isothiocyanate.

Suitable aryl carbamates may be of the form WCO₂Ar′ where W is forexample

and Ar′ may be for example 4-nitrophenyl.

Synthesis of the Compounds of Table 1

As an illustrative example of the synthesis of the compounds shown inTable 1, the synthesis of Example 1 from Table 1, is provided below:

N-[6{(Naphthalen-2-ylmethyl) -amino}-hexyl]-2-nitrobenzenesulfonamideStep A, Scheme 1 [6-(2-Nitrobenzenesulfonylamino)-hexyl]-carbamic acidt-butyl Ester

To a stirred solution of N-Boc 1,6-diaminohexane hydrochloride (1.51 g,6 mmol) and triethyle amine (1.31 g, 13 mmol) in 50 mL methylenechloride was added 2-Nitrobenzenesulfonyl chloride (1.326 g, 6 mmol).The reaction mixture was stirred for 6 h at room temperature, quenchedwith brine, and extracted with methylene chloride (2×50 mL). The organiclayer was washed with brine (a saturated solution of sodium chloride inwater, unless otherwise specified), dried over anhydrous sodium sulfate,and concentrated in vacuo to yield the titled compound as yellow oil(2.1 g, 87%).

Step B, Scheme 1 N-(6-Aminohexyl)-2-nitrobenzenesulfonamideHydrochloride

To a stirred solution of[6-(2-Nitrobenzenesulfonylamino)-hexyl]-carbamic acid t-butyl ester (2.0g, 4.9 mmol) in 25 mL of methylene chloride at room temperature wasadded 3 mL of saturated HCl solution in ethyl acetate and stirred for 4h. The precipitated solid was filtered to yield the titled compound aswhite solid (1.58 g, 95%); mp 161-162° C.

Step C, Scheme 1N-[6{(Naphthalen-2-ylmethyl)-amino}-hexyl]-2-nitrobenzenesulfonamide

A mixture of N-(6-Aminohexyl)-2-nitrobenzenesulfonamide hydrochloride(0.67 g, 2.0 mmol) and 2-naphthaldehyde (0.32 g, 2.1 mmol) in 75 mL oftoluene was refluxed using a Dean Stark trap for 20 h. The reactionmixture was concentrated in vacuo. The residue was dissolved in ethanol(40 mL) and sodium borohyride (0.020 g, 6.0 mmol) was added. After thereaction was complete (6 h), the solvent was evaporated and residuetaken up in 30 mL of saturated sodium chloride solution and extractedwith ethyl acetate (3×40 mL), washed with saturated sodium chloridesolution, dried over sodium sulfate and concentrated to afford an oil.The oil was flash chromatographed over silica gel to afford the titledcompound (0.16 g, 37%) which was converted into hydrochloride salt (mp169° C.).

An example of the use of the alternative path to the compounds ofFormula 1-2 by reduction of the amide of Formula 1-3 using borane-THFcomplex as previously described for Scheme 1, Step E, is provided forExample 15 of Table 1, as follows:

N-[6{(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-amino}-hexyl]-2-aminobenzenesulfonamide

To a solution of 1,2,3,4-tetrahydro-2-naphthalencarboxylicacid[6-(2-nitrobenzenesulfonylamino)-hexyl]-amide (0.090 g, 0.19 mmol)in tetrahydrofuran (5 mL) cooled to 0° C. was added 2 mL 1M solution ofborane:THF complex and the reaction mixture was refluxed for 12 h. Thereaction mixture was cooled in an ice bath and quenched with 2 mL of 1NHCl. The reaction mixture was neutralized with 10% aqueous sodiumhydroxide solution and extracted with ethyl acetate (3×25 mL). Theorganic phase was washed with brine, dried over sodium sulfate, andevaporated in vacuo to afford an oil which was purified by preparativeTLC to afford the titled compound (0.06 g, 70%); hydrochloride salt mp(162-163° C.).

Using appropriately substituted starting materials, the other Examplesshown in Table 1 were synthesized as described above, with the exceptionof Example 52. The compound of Example 52 in Table 1 was synthesizedsimilarly, except that before deprotection of the amine of Formula 1-1in Scheme 1 Step B, the sulfonyl nitrogen was alkylated with methyliodide in dimethylformamide at room temperature to afford theN-methylated sulfonamide product (Sato et al., 1995), which wassubsequently deprotected as in Scheme 1, Step B, for use in theremainder of Scheme 1.

Other n-alkyl derivatives may be prepared similarly, using an n-alkylhalide in an inert solvent such as dimethylformamide as described above.

TABLE 1 No. Ar X R₁ L K W mp Analysls  1

— H —(CH₂)₅— CH₂NHCH₂

169 C₂₃H₂₆N₃O₄S + HCl + 0.05 CHCl₃  2

— H —(CH₂)₅— CH₂NHCH₂

174 C₂₇H₃₀N₂O₂S + HCl  3

— H —(CH₂)₄— CH₂NHCH₂

194-5 C₂₆H₂₈N₂O₄S + HCl + 0.04 CHCl₃  4

— H —(CH₂)₅— CH₂NHCH₂

190-1 C₂₇H₃₀N₂O₂S + HCl  5

— H —(CH₂)₅— CH₂NHCH₂

149-50  6

— H —(CH₂)₅— CH₂NHCH₂

158 C₂₄H₂₇N₂O₂SF₃ + HCl  7

— H —(CH₂)₅— CH₂NHCH₂

111-12 —  8

— H —(CH₂)₅— CH₂NHCH₂

139 C₂₁H₂₉N₃O₆S + HCl + 0.1H₂O  9

— H —(CH₂)₅— CH₂NHCH₂

172-4 C₂₄H₂₇N₂O₂SF₃ + HCl 10

— H —(CH₂)₅— CH₂NHCH₂

167 C₂₄H₂₈N₂O₂SF₃ + HCl 11

— H —(CH₂)₅— CH₂NHCH₂

139-40 C₂₇H₃₁N₂O₂S + HCl 12

— H —(CH₂)₅— CH₂NHCH₂

194-6 C₂₃H₂₆N₂O₂S + HCl 13

— H —(CH₂)₅— CH₂NHCH₂

119-20 C₂₅H₃₀N₂O₄S + HCl 14

— H —(CH₂)₅— CH₂NHCH₂

120-1 C₂₄H₃₀N₂O₃S + HCl 15

— H —(CH₂)₅— CH₂NHCH₂

162-63 C₂₃H₃₂N₃O₂S + 2.0 HCl 16

— H —(CH₂)₅— CH₂NHCH₂

141 C₂₄H₃₆N₃O₄S + HCl + 0.1CH₂Cl₂ 17

— H —(CH₂)₅— CH₂NHCH₂

183-6 C₂₃H₂₇N₃O₄S + HCl 18

— H —(CH₂)₅— CH₂NHCH₂

181-4 19

— H —(CH₂)₇— CH₂NHCH₂

158 C₂₆H₃₁N₃O₄S + HCl 20

— H —(CH₂)₇— CH₂NHCH₂

145-6 C₂₉H₃₄N₂O₂S + HCl 21

— H —(CH₂)₇— CH₂NHCH₂

117-20 C₂₆H₃₀N₃O₄SF₃ + HCl 22

— H —(CH₂)₇— CH₂NHCH₂

153-5 C₂₅H₃₃N₃O₂SF₃ + HCl 23

— H —(CH₂)₇— CH₂NHCH₂

166-8 C₂₅H₃₃N₃O₂S + 2.0 HCl 24

— H —(CH₂)₇— CH₂NHCH₂

120-2 C₂₆H₃₄N₂O₃S + HCl + 0.05 CHCl₃ 25

— H —(CH₂)₇— CH₂NHCH₂

134-6 C₂₅H₃₅N₃O₄S + HCl 26

— H —(CH₂)₇— CH₂NHCH₂

129-31 C₂₅H₃₇N₃O₂S + 2.0 HCl 27

— H —(CH₂)₇— CH₂NHCH₂

113-4 C₂₆H₃₈N₃O₃S + HCl + 0.1 CHCl₃ 28

— H

CH₂NHCH₂

250-1 C₂₉H₃₂N₃O₂S + HCl 29

— H

CH₂NHCH₂

195 C₂₉H₃₁N₂O₂S + HCl + 0.25 H₂O 30

— H

CH₂NHCH₂

172 C₂₉H₃₂N₂O₂S + HCl + 0.25 CH₂Cl₂ 31

— H

CH₂NHCH₂

210 C₂₉H₃₆N₂O₂S + HCl 32

— H

CH₂NHCH₂

220 C₂₉H₃₆N₂O₂S + HCl + 0.15 CH₂Cl₂ 33

— H

CH₂NHCH₂

201 C₂₉H₃₂N₂O₂S + HCl + 0.3 CHCl₃ 34

— H

CH₂NHCH₂

194-5 C₂₅H₂₉N₃O₄S + HCl + 0.1 CHCl₃ 35

— H

CH₂NHCH₂

Hygroscopic C₂₅H₂₉N₃O₄S + HCl + 0.2 C₆H₁₄ 36

— H

CH₂NHCH₂

200-2 C₂₅H₃₃N₃O₄S + HCl 37

— H

CH₂NHCH₂

216-7 C₂₆H₂₉N₂O₂SF₃ + HCl 38

— H

CH₂NHCH₂

171-4 C₂₆H₂₉N₂O₂SF₃ + HCl + 0.075 CHCl₃ 39

— H

CH₂NHCH₂

75-8 C₂₆H₃₃N₂O₂SF₃ + HCl + 0.05 CHCl₃ 40

— H

CH₂NHCH₂

175-7 C₂₆H₃₅N₃O₂S + 2 HCl + 0.8 Et₂O 41

— H

CH₂NHCH₂

Hygroscopic C₂₆H₂₉N₃O₂S + HCl 42

— H

CH₂NHCH₂

118-20 C₂₆H₂₉N₃O₂S + 2.6 HCl 43

— H

CH₂NHCH₂

115 dec C₂₃H₃₁N₆O₄S + 2.4 HCl 44

— H

CH₂NHCH₂

89 dec C₂₄H₂₈N₄O₄S + 2 HCl 45

— H

CH₂NHCH₂

104-6 C₂₄H₂₈N₄O₄S + 2 HCl + 0.25 CHCl₃ 46

— H

CH₂NHCH₂

78-80 C₂₄H₃₂N₄O₄S + 2 HCl + 0.65 CHCl₃ 47

— H

CH₂NHCH₂

249-51 C₂₃H₂₉N₃O₆S + HCl + 0.1 CHCl₃ 48

— H

CH₂NHCH₂

220-21 C₂₂H₂₇N₃O₆S + HCl + 0.05 CHCl₃ 49

— H

CH₂NHCH₂

62-5 C₂₃H₃₁N₃O₆S + HCl + 0.5 CHCl₃ 50

— H

CH₂NHCH₂

196-7 C₂₄H₃₁N₃O₅S + HCl 51

— H

CH₂NHCH₂

57 C₂₅H₃₃N₃O₅S + HCl + 0.13 CHCl₃ 52

— CH₃

CH₂NHCH₂

235-6 C₃₀H₃₄N₂O₂S + HCl

Synthesis of the Compounds of Table 2

As an illustrative example of the synthesis of the compounds shown inTable 2 as shown in Scheme 1, Step D, the synthesis of Example 53 fromTable 2, is provided below:

1,2,3,4-Tetrahydro-2-naphthalencarboxylicAcid[6-(2-nitrobenzenesulfonylamino)-hexyl]-amide Step D, Scheme 11,2,3,4-Tetrahydro-2-naphthalencarboxylicAcid[6-(2-nitrobenzenesulfonylamino)-hexyl]-amide

A mixture of N-(6-aminohexyl)-2-nitrobenzenesulfonamide hydrochloride(0.2 g, 0.58 mmol), EDC (0.252 g, 1.31 mmol), and DMAP (0.14 g, 1.21mmol) in methylene chloride (30 mL) was stirred at room temperature for0.5 h. 1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (0.114 g, 0.65mmol) was added to the reaction mixture and stirred at room temperatureuntil the completion of the reaction (determined by TLC). The reactionmixture was washed with saturated ammonium chloride (3×30 mL), driedover sodium sulfate and concentrated in vacuo. The residue was flashchromatographed over silica gel to afford an oil (0.25 g, 93%).

Other compounds of Formula 1-3, as shown in Table 2, were synthesizedusing the methods described above, except for Examples 59 and 63.Example 59 was synthesized as shown in Scheme 1, except for the use ofsulfamyl chloride starting material Ar—NH—SO₂Cl instead of the sulfonylchloride Ar—SO₂Cl (Benson and Spillane, Chem, Rev. 80:151-186, 1980).

Example 63 of Table 2 was synthesized from the compound of Example 53 ofTable 2 by reduction of the aryl nitro moiety using tin chloride inHCl/Acetic acid/H₂O at room temperature, to afford the amino arylderivative (such as in Example 56, Table 2), which was then sulfonylatedwith alkyl sulfonyl chloride to afford the bis-sulfonylated compound ofExample 63 as follows:

1,2,3,4-Tetrahydro-2-naphthalencarboxylicacid[6-{2-(bismethanesulfonylaminobenzenesulfonylamino)}-hexyl]-amide(a) 1,2,3,4-Tetrahydro-2-naphthalencarboxylicacid[6-(2-aminobenzenesulfonylamino)-hexyl]-amide

To a solution of 1,2,3,4-Tetrahydro-2-naphthalencarboxylic acid[6-(2-nitrobenzenesulfonylamino)-hexyl]-amide (0.54 g, 1.17 mmol) in 5 mLof glacial acetic acid stirred at 0° C. was added a solution of tinchloride (1.32 g, 5.88 mmol)in 5 mL conc. HCl and 1 mL of water. Thereaction mixture was warmed to room temperature and stirred for 3 h andpoured over crushed ice (50 g). The reaction mixture was neutralizedwith 10% sodium hydroxide and extracted with chloroform (5×50 mL), driedover sodium sulfate and concentrated to afford yellow oil (0.48 g, 95%).

(b) 1,2,3,4-Tetrahydro-2-naphthalencarboxylicacid[6-{2-(bismethanesulfonylaminobenzenesulfonylamino)}-hexyl]-amide

To a solution of 1,2,3,4-tetrahydro-2-naphthalencarboxylicacid[6-(2-aminobenzenesulfonylamino)-hexyl]-amide (0.075 g, 0.17 mmol)in chloroform (3 mL), and triethylamine (0.1 g, 1 mmol)stirred at 0° C.was added methane sulfonyl chloride (30 mL, 0.35 mmol) and the reactionmixture was stirred at room temperature for 3 h. Solvent was evaporatedand purifications by preparative TLC afforded the titled compound aswhite solid (0.1 g, 97%); mp 70° C.

The amine of Example 56, Table 2, further may be acylated in the samemanner as above in Example 63 but using suitable alkyl acyl chloridesinstead of an alkyl sulfonyl chloride.

TABLE 2 No. Ar X R₁ L K W mp Analysis 53

— H —(CH₂)₅— CH₂NHCO

Oil C₂₃H₂₉N₃O₅S + 0.35CH₂Cl₂ 54

— H —(CH₂)₅— CH₂NHCO

Oil C₂₄H₃₂N₂O₄S + 0.6 CHCl₃ 55

— H —(CH₂)₅— CH₂NHCO

Oil C₂₄H₂₆N₃O₅SF₃ + 0.2 C₆H₁₄ 56

— H —(CH₂)₅— CH₂NHCO

72-4 C₂₃H₃₁N₃O₃S + 0.25 CH₂Cl₂ 57

— H —(CH₂)₅— CH₂NHCO

132 C₂₃H₂₆N₄O₅SF₃ + HCl + 0.05 CHCl₃ 58

— H —(CH₂)₅— CH₂NHCO

98 C₂₂H₂₉N₄O₅S + HCl + 0.1 CHCl₃ 59

NH H —(CH₂)₄— CH₂NHCO

Oil C₂₂H₂₉N₄O₅S + 0.35 CH₂Cl₂ 60

— H —(CH₂)₅— CH₂NHCO

Oil C₂₃H₂₅N₃O₅S 61

— H —(CH₂)₅— CH₂NHCO

105 C₂₃H₂₅N₃O₅S 62

— H —(CH₂)₇— CH₂NHCO

Oil C₂₅H₃₃N₃O₅S + 0.15 CHCl₃ 63

— H —(CH₂)₅— CH₂NHCO

70 C₂₅H₃₅N₃O₇S₃ 64

— H

CH₂NHCO

194-7 C₂₅H₃₃N₃O₃S + HCl + 0.2 CHCl₃ 65

— H

CH₂NHCO

78-80 C₂₅H₃₉N₃O₆S + HCl + 0.3 CHCl₃ 66

— H

CH₂NHCO

86-87 C₂₉H₃₂N₂O₄S + HCl + 0.35 CHCl₃ 67

— H

CH₂NHCO

59-61 C₂₉H₃₂N₂O₄S + 0.2 CHCl₃ 68

— H

CH₂NHCO

150-3 C₂₃H₂₅N₅O₅S + 0.25 CHCl₃ 69

— H

CH₂NHCO

62-4 C₂₄H₂₆N₄O₅S + 0.3 CHCl₃ 70

— H

CH₂NHCO

85-7 C₂₇H₃₇N₃O₇S₃ + 0.25 CHCl₃

Synthesis of the compounds of Table 3

As an illustrative example of the synthesis of the compounds shown inTable 3 and Table 3a, as shown in Scheme 1, Step F, the synthesis ofExample 71 from Table 3, is provided below:

Synthesis of Naphthalene-1-sulfonicacid{6-[3-(1-naphthyl)-uriedo]-hexyl}-amide Step F, Scheme 1

To a solution of N-(6-aminohexyl)-1-naphthalenesulfonamidehydrochloride(0.1 g, 0.29 mmol) in 3 mL dimethylformamide and 50 mLN-methyl morpholine was added 1-naphthalene isocynate(68 μL, 0.4 mmol).The reaction mixture was stirred at room temperature for 6 h. Solventwas evaporated in vacuo and residue was purified by preparative TLC toafford white solid(110 mg, 79%);mp 105-106° C.

An example of the synthesis of a compound of Formula 1-4 in Scheme 1,using an aryl carbamate as previously described, is provided for Example74 of Table 3, as follows:

3, 4-Dihydroquinoline-1-carboxylicacid[6-(2-trifluoromethylbenzenesulfonylamino)-hexyl]amide (a) 3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester

To a solution of tetrahydroisoquinoline (3.99 g, 30 mmol) in triethylamine(6 g, 60 mmol) and dichloromethane(150 mL) cooled in ice bath wasadded p-nitrophenyl chloroformate (6.06 g, 30 mmol) drop wise over aperiod of 1 h. The reaction mixture was srirred at room temperature for3 h and then washed with water (3×100 mL), dried over sodium sulfate andconcentrated to afford an oil which was triturated with ether:hexane toafford the titled compound as yellow solid (5.9 g, 65%).

(b) 3, 4-Dihydroquinoline-1-carboxylicacid[6-(2-trifluoromethylbenzenesulfonylamino)-hexyl]amide:

To a solution of N-(6-Aminohexyl) -2-trifluoromethylbenzene sulfonamideHydrochloride( 0.1 g, 0.27 mmol) dimethyl formamide (3 mL) andtriethylamine (0.1 g, 1 mmol) was added 3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester (0.09 g,0.3 mmol) and the reaction mixture was stirred at room temperature for 4h. Solvent was evaporated and purification by preparative TLC afford thetitled compound as an oil (0.08 g, 61%).

Synthesis of the compounds of Table 3a

As illustrative examples of the synthesis of the compounds of Table 3a,as shown in Scheme 1, Step F, the syntheses of Examples 80-82 and 87 isprovided below:

Example 80 1-[1-(Naphthalene-1-sulfonyl)-piperidine-4-ylmethyl]-3-naphthalene-1-ylmethylthiourea1-Naphthalene-1-ylmethyl-3-piperidine-4-ylmethylthiourea

To a solution of 1-naphthalenemethylisothiocyanate (2.8 g, 13.6 mmol) in100 ml of MeOH-THF solution (1:1 mixture) was added4-aminomethylpiperidine (3.1 ml, 27.0 mmol) in a portion and theresulting solution was stirred at reflux for 12 h. The reaction mixturewas concentrated in vacuo, yielding oily mixture which was subjected tocolumn chromatography (10% MeOH/CHCl₃) to yield 2.3 g (48%) of thedesired product as an oil.

1-[-(Naphthalene-1-sulfonyl)-piperidine-4-ylmethyl]-3-naphthalene-1-ylmethylthiourea

To a solution of the amine (0.34 g, 1.1 mmol) in 10 ml of pyridine wasadded 1-naphthalenesulfonyl chloride (0.30 ml, 1.3 mmol) in a portionand the resulting mixture was stirred at 25° C. for 12 h. The reactionmixture was subjected to column chromatography (50% Hexane/EtOAc) toyield 0.21 g (38%) of the desired product as yellow solid, which wasrecrystallized from EtOAc to provide 0.15 g of the product as whitesolid: mp 83-85° C.; Anal. Cal. For C₂₈H₂₉N₃O₂S₂ requires C, 66.77; H,5.80; N, 8.34. Found: C, 64.32; H, 5.89; N, 8.27.

Example 812-methyl-1-[1-(naphthalene-1-sulfonyl)piperidine-4-ylmethyl]-3-naphthalene-1-ylmethylisothiourea

To a solution of the thiourea of Example 80 (0.11 g, 0.32 mmol) in MeOHwas added MeI (0.5 ml, 8.1 mmol) in a portion and the resulting mixturewas stirred at 25° C. for 12 h. The reaction mixture was concentrated invacuo, yielding a solid which was recrystallized from EtOH to yield 0.11g (53%) of the desired product as white solid: mp 111-113° C.; Anal.Cal. For C₂₉H₃₁N₃O₂S₂. 1.0 HI requires C, 54.04; H, 4.89; N, 6.52.Found: C, 52.97; H, 5.01; N, 6.47.

Example 821-[1-(Naphthalene-1-sulfonyl)-piperidine-4-ylmethyl]-3-naphthalene-1-ylmethylurea1-Naphthalene-1-ylmethyl-3-piperidine-4-ylmethylurea

To a solution of 1-naphthalenemethylcyanate (1.1 g, 6.0 mmol) in 50 mlof CHCl₃ was added 4-aminomethylpiperidine (0.9 ml, 7.8 mmol) in aportion and the resulting solution was stirred at reflux for 12 h. Thereaction mixture was concentrated in vacuo, yielding oily mixture whichwas purified on column chromatography (5% MeOH/CHCl₃) to yield thedesired product 1.6 g (89%) of the desired product as an oil.

1-[1-(Naphthalene-1-sulfonyl)-piperidine-4-ylmethyl]-3-naphthalene-1-ylmethylurea

To a solution of the amine (0.60 g, 2.0 mmol) in 30 ml of pyridine wasadded 1-naphthalenesulfonyl chloride (0.60 ml, 2.7 mmol) in a portionand the resulting mixture was stirred at 25° C. for 12 h. The reactionmixture was 10 subjected to column chromatography (CHCl₃, neat) to yield0.63 g (65%) of the desired product as light yellow solid, which wasrecrystallized from EtOAc to provide 0.37 g of the product as whitesolid: mp 103-104° C.; Anal. Cal. For C₂₈H₂₉N₃O₃S requires C, 64.97; H,5.99; N, 8.62. Found: C, 66.03; H, 5.83; N, 8.49.

Example 871-Naphthalene-1-ylmethyl-3-[1-(2-trifluoromethylbenzenesulfonyl)-pyrrolidin-3-yl]-urea1-(Naphthalene-1-sulfonyl) -pyrrolidin-3 -ylamine

To a solution of 1-naphthalenesulfonyl chloride (1.0 g, 5.4 mmol) in 50ml of CH₂Cl₂ with 2 ml of trimethylamine was added3-t-butoxycarbonylpyrrolidine (1.5 g, 6.5 mmol) in a portion and theresulting solution was stirred at reflux for 48 h. Reaction mixture wasconcentrated in vacuo, yielding oily mixture which was partioned between100 ml of EtOAc and NaHCO₃ sat'd aqueous solution. Organic layer wasseparated, dried over Na₂SO₄ and concentrated in vacuo to provide anoil, which was redissolved in 20 ml of CH₂Cl₂. Toward this solution wasadded 1 ml of trifluoroacetic acid and the resulting solution wasstirred for 2 h at 25° C. Reaction mixture was concentrated in vacuo,providing a brown oil, which was dissolved in EtOAc and washed withaqueous NaOH. organic layer was concentrated in vacuo to yield an oilwhich was subjected to column chromatography (30% MeOH/CHCl₃) to provide0.17 g (23%) of the desired product.

1-Naphthalene-1-ylmethyl-3-[1-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidin-3-yl]-urea

The amine (37 mg, 0.12 mmol) and naphthalene-1-ylmethyl-carbamic acid4-nitro-phenyl ester (61 mg, 0.19 mmol) in 5 ml of CH₂Cl₂ was stirred at25° C. for 12 h . The reaction mixture was subjected to columnchromatography (2% MeOH/CHCl₃) to yield 42 mg (74%) of the desiredproduct as light yellow solid: mp 117-119° C.; Anal. Cal. ForC₂₃H₂₂F₃N₃O₃S requires C, 57.85; H, 4.64; N, 8.80. Found: C, 56.16; H,4.71; N, 8.67.

Additional compounds may be synthesized by substitution of appropriatestarting materials, and are not intended to be limited to thosecompounds shown in Table 3a.

Other compounds of Formula 1-4, as shown in Table 3 and Table 3a, weresynthesized using the methods described above, using appropriatelysubstituted starting materials.

TABLE 3 No. Ar X R₁ L K W mp Analysis 71

— H —(CH₂)₅— CH₂NHCONH

105-06 C₂₇H₂₉N₃O₃S 72

— H —(CH₂)₅— CH₂NHCONH

115 C₂₃H₂₆N₄O₅S 73

— H —(CH₂)₅— CH₂NHCONH

Oil C₂₄H₂₉N₃O₄S + 0.5 CHCl₃ 74

— H —(CH₂)₅— CH₂NHCO

Oil C₂₃H₂₈N₃O₃S

TABLE 3a No. Ar X L K W mp 81

—

111-113 C₂₉H₃₁N₃O₂S + HI 80

—

83-85 C₂₈H₂₉N₃O₂S₂ 82

—

104-106 C₂₈H₂₉N₃O₃S 83

—

176-178 C₂₅H₂₇N₃O₄S₂ 84

—

199-201 C₂₅H₂₇N₃O₄S₂ 85

—

94-97 C₂₅H₂₆F₃N₃O₃S 86

—

88-90 C₂₅H₂₆F₃N₃O₂S₂ 87

—

117-119 C₂₃H₂₂F₃N₃O₃S 88

—

162-164 C₂₄H₂₆N₄O₅S

Synthesis of compounds of Scheme 2

Compounds in which L is substituted may be produced according to Scheme2. The carbobenzyloxy-protected amino acid derivative of L may beesterified by thionyl chloride and methanol as shown in Scheme 2, StepA, and the ester subsequently reduced by diisobutylaluminum hydride inTHF as shown in Scheme 2, Step B, at −78° C., to yield alcohol, which isthen oxidized by pyridinium chlorochromate in Scheme 2, Step C, in asuitable solvent such as CH₂Cl₂, to afford an aldehyde of Formula 2-1.The aldehyde may be treated with ammonia, and then trimethylsilylcyanide(Chakraborty, et al. Tet. Lett. 32(51):7597-7600, 1991) as shown inScheme 2, Step D, in a suitable solvent such as methanol, to yield thecompound of Formula 2-2. The compound of Formula 2-2 may be subjected tosulfonylation as described above in Scheme 1, Step A, to yield thecompound of Formula 2-3. The cyano moiety of the compound of Formula 2-3may be esterified and deblocked to afford compounds of Formula 2-4; orif desired, the compound of Formula 2-3 may be further reduced, orhydrolyzed as appropriate to yield substituted compounds other thanthose shown in Formula 2-5, which compounds may be further used in anyof Steps C, D, E, or F of Scheme 1.

An example of the synthesis of a compound of Formula 2-5 is thesynthesis of compound 79:

7-[Naphthalen-2-ylmethyl)-amino]-2-(2-nitrobenzenesulfonylamino)-heptanoicacid methyl ester (a) Step A, Scheme 2 6-Benzyloxycarbonylamino-hexanoicAcid Methyl Ester:

To a solution of 6-benzyloxycarbonylamino-hexanoic acid (10 g, 38 mmol)in methanol (200 mL) at room temperature was added thionyl chloride (11g, 95 mmol). The reaction mixture was then refluxed for 16 h. Thesolvent was concentrated in vacuo, the residue was dissolved in ethylacetate (200 mL) and washed with brine (3×150 mL), dried over anhydrousmagnesium sulfate, and concentrated in vacuo. The residue was- purifiedby flash column chromatography (silica, 14% ethyl acetate in hexane) toafford the titled compound (6.2 g, 58%), a colorless liquid.

(b) Step B, Scheme 2 (6-Hydroxyhexyl)-carbamic acid benzyl ester:

To a solution of diisobutylaluminum hydride (49 mL, 1.5 M in toluene) inTHF (150 mL) cooled to −78° C. was added a solution of6-benzyloxycarbonylamino-hexanoic acid methyl ester (10 g, 37 mmol) inTHF (100 mL) . The reaction mixture was stirred for 4 h and methanol(2.5 mL) was added carefully at −78 to −75° C. After 2 h, the mixturewas poured to 250 mL of 1 N HCl solution cooled in ice-bath, extractedwith ethyl acetate (300 mL), washed with brine (3×100 mL), dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue waspurified by flash column chromatography (silica, 50% ethyl acetate inhexane) to yield the titled compound (7.1 g, 80%); white solid, mp67-68° C.

(c) Step C, Scheme 2 (6-Oxy-hexyl)-carbamic acid benzyl ester:

To a suspension of pyridinum chlorochromate (9.2 g, 43 mmol) and celite(37 g) in methylene chloride (400 mL) was added(6-hydroxyhexyl)-carbamic acid benzyl ester (7.1 g, 24 mmol). Themixture was stirred for 3 h and dry ethyl ether (500 mL) was added toit. The mixture was stirred for additional 0.5 h, filtered through a padof celite and concentrated in vacuo. The residue was purified by flashcolumn chromatography (silica, 10-25% ethyl acetate in hexane) to yieldthe titled compound (4.8 g, 79%); colorless light oil.

(d) Step D, Scheme 2 (6-Amino-6-cyano-hexyl)-carbamic acid benzyl ester:

Ammonia was bubbled through a stirred solution of (6-oxy-hexyl}-carbamicacid benzyl ester (6.0 g, 24 mmol) in methanol (200 mL) for 2 h andTMSCN (2.9 g, 28 mmol) was added dropwise. The reaction mixture wasstirred for 24 h. The solvent was evaporated in vacuo. The residue waspurified by flash column chromatography (silica, 90-100% ethyl acetatein hexane) to yield the titled compound (4.3 g, 65%); light yellow oil.

(e) (Step A, Scheme 1) (6-Benzenesulfonylamino-6-cyano-hexyl) -carbamicacid benzyl ester:

Using the general procedure described in step A of scheme 1,(6-amino-6-cyano-hexyl}-carbamic acid benzyl ester (2.8 g, 10 mmol) wassulfonylated with 2-nitrobenzenesulfonyl chloride (2.5 g, 11 mmol) at 0°C. to yield the titled compound (1.7 g, 36%); yellow oil.

(f) Step E, Scheme 2 7-Amino-2 -nitrobenzenesulfonylamino-heptanoic acidmethyl ester:

Dry HCl gas was bubbled to a stirred solution of(6-benzenesulfonylamino-6-cyano-hexyl}-carbamic acid benzyl ester (0.58g, 1.3 mmol) in dry methanol (50 mL) for 2 h. The reaction mixture wascooled and solvent was evaporated in vacuo. Water (40 mL) was added tothe reaction mixture and neutralized with 1 N NaOH to pH 9-10, extractedwith ethyl acetate (4×100 mL), washed with brine (3×100 mL), dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue waspurified by preparative TLC (silica, 10% ammonia (2.0 M in methanol) inchloroform) to yield the titled compound (0.047 g, 10%); yellow thickoil.

(g) (Steps C, D, E, F, Scheme 1)7-[(Naphthalen-2-ylmethyl)-amino]-2-(2-nitrobenzenesulfonylamino)-heptanoicacid methyl ester:

Using the general procedure described in Steps C, D, E, and F of Scheme1, 7-amino-2-nitrobenzenesulfonylamino-heptanoic acid methyl ester(0.060 g, 0.17 mmol) was reductively aminated with 2-naphthaldehyde(0.026 g, 0.017 mmol) to afford the titled compound (0.050 g, 60%);yellow oil.

Synthesis of compounds according to Scheme 3

Other compounds of the present invention may be synthesized according toScheme 3. After protection of H₂N—L—COOH with Boc anhydride in CH₂Cl₂,as shown in Scheme 3, Step A, the protected amine may be amidated withW-K′″ as in Scheme 3, Step B, where K′″ is an alkylamino ester, usingEDC and DMAP in a suitable solvent such as CH₂Cl₂, to yield compounds ofFormula 3-1, where K′″ and the carboxylic acid carbonyl of H₂N—L—COOHtogether form K. The compounds of Formula 3-1 may be deprotected usingwell known methods as shown in Scheme 3, Step C, and furthersulfonylated with a sulfonyl halide of Ar, as shown in Scheme 3, Step D,in a suitable solvent such as CH₂Cl₂ and a tertiary amine such astriethylamine, to form the compound of Formula 3-2. The compounds ofFormula 3-2 may be reduced to yield the compounds of Formula 3-3, asshown in Scheme 3, Step E, using borane-tetrahydorfuran (THF) complex,in THF, at elevated temperature in an inert atmosphere.

A specific example of such a synthesis using Scheme 3 is provided belowfor Example 75 from Table 4:

trans-3-(4-Chloro-phenyl)-2-({[4-(naphthalene-1-sulfonylamino)-methyl]-cyclohexanecarbonyl}-amino]-propionicacid methyl ester: (a) Step A, Scheme 3 trans-4(tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid:

To a solution of trans-4 -(aminomethyl)cyclohexanecarboxylic acid (10 g,57 mmol) in 1 N NaOH (110 mL) cooled to 0° C. was added a solution ofdi-tert-butyl dicarbonate (15 g, 69 mmol) in dioxane (50 mL). Thereaction mixture was stirred at 0° C. for 12 h. The raction mixture wasneutralized by 1 N HCl solution to pH 3, extracted with ethyl ether(2×300 mL), washed with brine (2×300 mL), dried over anhydrous magnesiumsulfate, and concentrated in vacuo to afford the titled compound (16 g,100%); white solid, mp 128-9° C.

(b) Step B, Scheme 3-trans-2-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}3-(4-Chloro-phenyl)-propionicacid methyl ester:

Using the general procedure described for the preparation Step D, Scheme1, trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid(1.1 g, 4.0 mmol) was acylated with D,L-4-chlorophenylalanine methylester hydrochloride (1.0 g, 4.0 mmol) to afford the titled compound (1.9g, 99%); white solid, mp 178-9° C.

(c) Step C, Scheme 3trans-2-[4-(Aminomethyl-cyclohexanecarbonyl)-amino]3-(4-chloro-phenyl)-propionicacid methyl ester hydrochloride:

Using the general procedure described in step b scheme 1,trans-2-{[4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarbonyl]-amino}3-(4-chloro-phenyl)-propionicacid methyl ester (1.8 g, 4.3 mmol) was deprotected using HCl in ethylacetate to afford the titled compound; light yellow solid mp 146-9° C.

(d) Step D, Scheme 3trans-3-(4-Chloro-phenyl)-2-({[4-(naphthalene-1-sulfonylamino)-methyl]-cyclohexanecarbonyl}-amino]-propionicacid methyl ester:

Using the general procedure described in example A scheme 1,trans-2-[4-(aminomethyl-cyclohexanecarbonyl)-amino]3-(4-Chloro-phenyl)-propionic acid methyl ester hydrochloride (0.35 g,0.86 mmol) was sulfonylated with 1-naphthalenesulfonyl chloride (0.42 g,91%) to afford the titled ompound; white solid, mp 84-6° C.

The compound of Example 77, Table 4, was synthesized from the abovecompound by borane-THF reduction as follows:

(e) Step E, Scheme 3 Naphthalene-1-sulfonic Acidtrans-(4-{[2-(4-Chloro-phenyl)-1-hydroxymethyl-ethylamino]-methyl}-cyclohexylmetbyl)-amide:

Using the general procedure described in Step H, Scheme 1,trans-3-(4-chloro-phenyl)-2-({[4-(naphthalene-1-sulfonylamino)-methyl]-cyclohexanecarbonyl}-amino]-propionicacid methyl ester (0.30 g, 0.55 mmol) was reduced by borane:THF complex(1.0 M in THF) to afford the titled compound; colorless oil.

Other compounds of Formula 3-3 or Formula 3-4, as shown in Table 4,where for example, K is substituted with an alcohol or ester, may alsobe synthesized using the methods of Scheme 3.

TABLE 4 No. Ar X R₁ L K W mp Analysis 75

— H

84-6 C₂₈H₃₁N₂O₅SCl + 0.4 CHCl₃ 76

— H

Oil C₂₄H₂₈N₃O₇SCl + 0.15 CHCl₃ 77

— H

223-3 C₂₇H₃₃N₂O₃SCl + HCl 78

— H

263-4 C₂₇H₃₃N₂O₃SCl + HCl

Synthesis of compounds 89 and 90

The synthesis of compounds such as 89 and 90 may be accomplished by themethod shown in Scheme 4, as described below:

Example 89 (a) 4-Oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid-(naphthalene-1-ylmethyl) -amide (Scheme 4, product 1)

A mixture of 1-naphthalenemethylamine (1.37 g, 7.2 mmol),4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.13 g, 7.2 mmol)ECD (2.87 g, 15 mmol), and DMAP (1.83 g, 15 mmol) in CH₂Cl₂ (20 mL) wasstirred at room temperature. After 12 h, the reaction mixture wasconcentrated and the residue was purified by flash column chromatography(2-5% MeOH in CH₃Cl to yield the product (2.29 g, 97% liht yellow solid,m.p. 155-156° C.).

(b)4-Cyano-4-trimethylsilanyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid-(naphthalen-1-ylmethyl)-amide (Scheme 4, product 2)

To a mixture of the product of step (a) (2.29 g, 6.95 mmol) and acatalytic amount of ZnI₂ in dry CH₂Cl₂ (50 mL) at 0° C. was addeddropwise TMSCN (1.4 g, 1.87 mL, 14 mmol) under argon. The reactionmixture was warmed to room temperature and stirred for 24 h. Afterconcentration of the reaction mixture, the residue was purified by flashcolumn chromatography (2-5% MeOH in CH₃Cl to yield the product (1.6 g,54%, 95% after recovering the product from (a); light yellow solid, m.p.55-56° C.).

(c)1-Aminomethyl-4-{[(naphthalene-1-ylmethyl)-amino]-methyl}-1,2,3,4-tetrahydronaphthalen-1-ol(Scheme 4, product 3)

To a solution of the product of step (b) (1.4 g, 3.27 mmol) in THF (30mL) was added dropwise 25 mL of BH₃-THF complex (1.0 M in THF) underargon. The reaction mixture was refluxed for 16 h. After cooling to 0°C., 6N HCl was added dropwise to the reaction mixture and the resultantmixture stirred for 24 h at room temperature. After cooling to 0° C.,this mixture was neutralized by 1N NaOH to pH 7 to 8, extracted withethyl acetate (100 mL), washed with water (60 mL×2), dried (Na₂SO₄), andconcentrated. The residue was purified by flash column chromatography(2-5% MeOH in CH₃Cl to yield the product (0.30 g, 27%, light yellowsolid).

(d)N-(1-hydroxy-4-{[(naphthalen-1-ylmethyl)-amino]-methyl}-1,2,3,4-tetrahydronaphthalen-1-ylmethyl-2-nitro-benzenesulfonamide(Scheme 4, product 4)

To a mixture of the product of step (c) (0.30 g, 0.866 mmol) and Et3N(0.35 g, 3.46 mmol) in dry CH₂Cl₂ (15 mL) at 0° C. was added dropwise asolution of 2-nitrobenzenesulfonyl chloride (0.19 g, 0.866 mmol) in dryCH₂Cl₂ (10 mL). The reaction mixture was warmed to room temperature andstirred for 6 h. After concentration of the reaction mixture, theresidue was purified by flash column chromatography (2-5% MeOH in CH₃Cl)to yield the product (0.43 g, 93%, light yellow solid.

Example 90

Scheme 4, product 5)

A mixture of the compound of Example 89 (0.35 g, 0.658 mmol) and TsOH(0.075 g, 0.395 mmol) in toluene was refluxed for 0.5 h. The reactionmixture was concentrated and purified by TLC chromatography (10% MeOH inCH₃Cl) to yield the product (0.217 g, 64%, light yellow solid, m.p.53-54° C.).

Pharmacological Evaluation of Compounds at Cloned Human NeuropeptideY-type Receptors.

The pharmacologic properties of the compounds of the present inventionwere evaluated at the cloned human neuropeptide Y-type receptors Y1, Y2,Y4, and Y5, or in in vivo studies in rats, using the protocols describedbelow.

MATERIALS AND METHODS

Cell Culture

COS-7 cells were grown on 150 mm plates in D-MEM with supplements(Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mMglutamine, 100 units/ml penicillin/100 μg/ml streptomycin) at 37° C., 5%CO₂. Stock plates of COS-7 cells were trypsinized and split 1:6 every3-4 days. Human embryonic kidney 293 cells were grown on 150 mm platesin D-MEM with supplements (minimal essential medium) with Hanks' saltsand supplements (Dulbecco's Modified Eagle Medium with 10% bovine calfserum, 4 mM glutamine, 100 units/ml penicillin/100 μg/ml streptomycin)at 37° C., 5% CO₂. Stock plates of 293 cells were trypsinized and split1:6 every 3-4 days. Mouse fibroblast LM(tk-) cells were grown on 150 mmplates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with10% bovine calf serum, 4 mM glutamine, 100 units/mL penicillin/100 μg/mLstreptomycin) at 37° C., 5% CO₂. Stock plates of LM(tk-) cells weretrypsinized and split 1:10 every 3-4 days.

LM(tk-) cells stably transfected with the human Y5 receptor wereroutinely converted from an adherent monolayer to a viable suspension.Adherent cells were harvested with trypsin at the point of confluence,resuspended in a minimal volume of complete DMEM for a cell count, andfurther diluted to a concentration of 10⁶ cells/ml in suspension media(10% bovine calf serum, 10% 10× Medium 199 (Gibco), 9 mM NaHCO₃, 25. mMglucose, 2 mM

L-glutamine, 100 units/ml penicillin/100 μg/mi streptomycin, and 0.05%methyl cellulose). The cell suspension was maintained in a shakingincubator at 37° C., 5% CO₂ for 24 hours. Membranes harvested from cellsgrown in this manner may be stored as large, uniform batches in liquidnitrogen. Alternatively, cells may be returned to adherent cell culturein complete DMEM by distribution into 96-well microtiter plates coatedwith poly-D-lysine (0.01 mg/ml) followed by incubation at 37° C., 5% CO₂for 24 hours. Cells prepared in this manner yielded a robust andreliable NPY-dependent response in cAMP radio-immunoassays as furtherdescribed hereinbelow.

Mouse embryonic fibroblast NIH-3T3 cells were grown on 150 mm plates inDulbecco's Modified Eagle Medium (DMEM) with supplements (10 bovine calfserum, 4 mM glutamine, 100 units/ml penicillin/100 μg/ml streptomycin)at 37° C., 5% CO₂. Stock plates of NIH-3T3 cells were trypsinized andsplit 1:15 every 3-4 days.

Sf9 and Sf21 cells were grown in monolayers on 150 mm tissue culturedishes in TMN-FH media supplemented with 10% fetal calf serum, at 27°C., no CO₂. High Five insect cells were grown on 150 mm tissue culturedishes in Ex-Cell 400™ medium supplemented with L-Glutamine, also at 27°C., no CO₂.

Transient Transfection

All receptor subtypes studied (human and rat Y1, human and rat Y2, humanand rat Y4, human and rat Y5) were transiently transfected into COS-7cells by the DEAE-dextran method, using 1 μg of DNA /10⁶ cells (Cullen,1987). The human Y1 receptor was prepared using known methods(Larhammar, et al., 1992).

Stable Transfection

Human Y1, human Y2, and rat Y5 receptors were co-transfected with aG-418 resistant gene into the human embryonic kidney 293 cell line by acalcium phosphate transfection method (Cullen, 1987). Stably transfectedcells were selected with G-418. Human Y4 and human Y5 receptors weresimilarly transfected into mouse fibroblast LM(tk-) cells and NIH-3T3cells.

Binding of the compounds of the present invention to the human Y1, Y2,Y4 and Y5 receptors was evaluated using stably transfected 293 orLM(tk-) cells as described above. Stably transfected cell lines whichmay be used for binding assays include, for example, for the human Y1receptor, 293-hY1-5 (deposited Jun. 4, 1996, under ATCC Accession No.CRL-12121), for the human Y2 receptor, 293-hY2-10 (deposited Jan. 27,1994, under ATCC Accession No. CRL-11537), for the human Y4 receptor,L-hY4-3 (deposited Jan. 11, 1995, under ATCC Accession No. CRL-11779),and for the human Y5 receptor, L-hY5-7 (deposited Nov. 15, 1995, underATCC Accession No. CRL-11995).

Expression of other G-protein coupled receptors

α₁ Human Adrenergic Receptors:

To determine the binding of compounds to human α₁ receptors, LM(tk-)cell lines stably transfected with the genes encoding the α_(1a),α_(1b), and α_(1d) receptors were used. The nomenclature describing theα₁ receptors was changed recently, such that the receptor formerlydesignated α_(1a) is now designated α_(1d), and the receptor formerlydesignated α_(1c) is now designated α_(1a) (ref). The cell linesexpressing these receptors were deposited with the ATCC before thenomenclature change and reflect the subtype desgnations formerlyassigned to these receptors Thus, the cell line expressing the receptordescribed herein as the α_(1a) receptor was deposited with the ATCC onSep. 25, 1992, under ATCC Accession No. CRL 11140 with the designationL-α_(1c). The cell line expressing receptor described herein as theα_(1d) receptor was deposited with the ATCC on Sep. 25, 1992, under ATCCAccession No. CRL 11138 with the designation L-α_(1A). The cell lineexpressing the α_(1b) receptor is designated L-α_(1B), and was depositedon Sep. 25, 1992, under ATCC Accession No. CRL 11139.

α₂ Human Adrenergic Receptors:

To determine the binding of compounds to human α₂ receptors, LM(tk-)cell lines stably transfected with the genes encoding the α_(2A),α_(2B), and α₂C receptors were used. The cell line expressing the α_(2A)receptor is designated L-α_(2A), and was deposited on Nov. 6, 1992,under ATCC Accession No. CRL 11180. The cell line expressing the α_(2B)receptor is designated L-NGC-α_(2B), and was deposited on Oct. 25, 1989,under ATCC Accession No. CRL 10275. The cell line expressing the α_(2C)receptor is designated L and was deposited on Nov. 6, 1992, under ATCCAccession No. CRL-11181. Cell lysates were prepared as described below(see Radioligand Binding to Membrane Suspensions), and suspended in 25mM glycylglycine buffer (pH 7.6 at room temperature). Equilibriumcompetition binding assay were performed using [³H]rauwolscine (0.5 nM),and nonspecific binding was determined by incubation with 10 μMphentolamine. The bound radioligand was separated by filtration throughGF/B filters using a cell harvester.

Human Histamine H₁ Receptor:

The coding sequence of the human histamine H₁ receptor, homologous tothe bovine H₁ receptor, was obtained from a human hippocampal cDNAlibrary, and was cloned into the eukaryotic expression vector pCEXV-3.The plasmid DNA for the H₁ receptor is designated pcEXV-H1, and wasdeposited on Nov. 6, 1992, under ATCC Accession No. 75346. Thisconstruct was transfected into COS-7 cells by the DEAE-dextran method.Cells were harvested after 72 hours and lysed by sonication in 5 mMTris-HCl, 5 mM EDTA, pH 7.5. The cell lysates were centrifuged at 1000rpm for 5 min at 4° C., and the supernatant was centrifuged at 30,000×gfor 20 min. at 4° C. The pellet was suspended in 37.8 mM NaHPO₄, 12.2 mMKH₂PO₄, pH 7.5. The binding of the histamine H₁ antagonist[³H]mepyramine (1 nM, specific activity: 24.8 Ci/mM) was done in a finalvolume of 0.25 mL and incubated at room temperature for 60 min.Nonspecific binding was determined in the presence of 10 AM mepyramine.The bound radioligand was separated by filtration through GF/B filtersusing a cell harvester.

Human Histamine H₂ Receptor:

The coding sequence of the human H₂ receptor was obtained from a humanplacenta genomic library, and cloned into the cloning site of PCEXV-3eukaryotic expression vector. The plasmid DNA for the H₂ receptor isdesignated pcEXV-H2, and was deposited on Nov. 6, 1992 under ATCCAccession No. 75345. This construct was transfected into COS-7 cells bythe DEAE-dextran method: Cells were harvested after 72 hours and lysedby sonication in 5 mM Tris-HCl, 5 mM EDTA, pH 7.5. The cell lysates werecentrifuged at 1000 rpm for 5 min at 4° C., and the supernatant wascentrifuged at 30,000×g for 20 min at 4° C. The pellet was suspended in37.8 mM NaHPO₄, 12.2 mM K2PO₄, pH 7.5. The binding of the histamine H₂antagonist [³H]tiotidine (5 nM, specific activity: 70 Ci/mM) was done ina final volume of 0.25 ml and incubated at room temperature for 60 min.Nonspecific binding was determined in the presence of 10 μM histamine.The bound radioligand was separated by filtration through GF/B filtersusing a cell harvester.

Human Serotonin Receptors:

5HT_(1Dα), 5HT_(1Dβ), 5HT_(1E), 5HT_(1F) Receptors: LM(tk-) clonal celllines stably transfected with the genes encoding each of these 5HTreceptor subtypes were prepared as described above. The cell line forthe 5HT_(1Dα) receptor, designated as Ltk-8-30-84, was deposited on Apr.17, 1990, and accorded ATCC Accession No. CRL 10421. The cell for the5HT_(1Dβ) receptor, designated as Ltk-11, was deposited on Apr. 17,1990, and accorded ATCC Accession No. CRL 10422. The cell line for the5HT_(1E) receptor, designated 5 HT_(1E)-7, was deposited on Nov. 6,1991, and accorded ATCC Accession No. CRL 10913. The cell line for the5HT_(1F) receptor, designated L-5-HT_(1F), was deposited on Dec. 27,1991, and accorded ATCC Accession No. ATCC 10957. Membrane preparationscomprising these receptors were prepared as described below, andsuspended in 50 mM Tris-HCl buffer (pH 7.4 at 37° C.) containing 10 mMMgCl₂, 0.2 mM EDTA, 10 M pargyline, and 0.1% ascorbate. The binding ofcompounds was determined in competition binding assays by incubation for30 minutes at 37° C. in the presence of 5 nM [³H]serotonin. Nonspecificbinding was determined in the presence of 10 μM serotonin. The boundradioligand was separated by filtration through GF/B filters using acell harvester.

Human 5HT₂ Receptor:

The coding sequence of the human 5HT₂ receptor was obtained from a humanbrain cortex cDNA library, and cloned into the cloning site of pCEXV-3eukaryotic expression vector. This construct was transfected into COS-7cells by the DEAE-dextran method. Cells were harvested after 72 hoursand lysed by sonication in 5 mM Tris-HCl, 5 mM EDTA, pH 7.5. This cellline was deposited with the ATCC on Oct. 31, 1989, designated asL-NGC-5HT₂, and was accorded ATCC Accession No. CRL 10287. The celllysates were centrifuged at 1000 rpm for 5 minutes at 4° C., and thesupernatant was centrifuged at 30,000×g for 20 minutes at 4° C. Thepellet was suspended in 50 mM Tris-HCl buffer (pH 7.7 at roomtemperature) containing 10 mM MgSO₄, 0.5 mM EDTA, and 0.1% ascorbate.The potency of alpha-1 antagonists at 5HT₂ receptors was determined inequilibrium competition binding assays using [3H]ketanserin (1 nM).Nonspecific binding was defined by the addition of 10 μM mianserin. Thebound radioligand was separated by filtration through GF/B filters usinga cell harvester.

Human 5-HT, Receptor:

A LM(tk-) clonal cell line stably transfected with the gene encoding the5HT₇ receptor subtype was prepared as described above. The cell line forthe 5HT₇ receptor, designated as L-5HT_(4B), was deposited on Oct. 20,1992, and accorded ATCC Accession No. CRL 11166.

Human Dopamine D₃ Receptor:

The binding of compounds to the human D3 receptor was determined usingmembrane preparations from COS-7 cells transfected with the geneencoding the human D₃ receptor. The human dopamine D₃ receptor wasprepared according to known methods (Sokoloff, P. et al. Nature, 347,146, 1990, deposited with the EMBL Genbank as X53944). Cells wereharvested after 72 hours and lysed by sonication in 5 mM Tris-HCl, 5 mMEDTA, pH 7.5. The cell lysates were centrifuged at 1000 rpm for 5minutes at 4° C., and the supernatant was centrifuged at 30,000×g for 20minutes at 4° C. The pellet was suspended in 50 mM Tris-HCl (pH 7.4)containing 1 mM EDTA, 5 mM KCl, 1.5 mM CaCl₂, 4 mM MgCl₂, and 0.1%ascorbic acid. The cell lysates were incubated with [³H]spiperone (2nM), using 10 μM (+)Butaclamol to determine nonspecific binding.

Membrane Harvest

Membranes were harvested from COS-7 cells 48 hours after transienttransfection. Adherent cells were washed twice in ice-cold phosphatebuffered saline (138 mM NaCl, 8.1 mM Na₂HPO₄, 2.5 mM KCl, 1.2 mM KH₂PO₄,0.9 mM CaCl₂, 0.5 mM MgCl₂, pH 7.4) and lysed by sonication in ice-coldsonication buffer (20 mM Tris-HCl, 5 mM EDTA, pH 7.7). Large particlesand debris were cleared by low speed centrifugation (200×g, 5 min, 4°C.). Membranes were collected from the supernatant fraction bycentrifugation (32,000×g, 18 min, 4° C.), washed with ice-cold hypotonicbuffer, and collected again by centrifugation (32,000×g, 18 min, 4° C.).The final membrane pellet was resuspended by sonication into a smallvolume of ice-cold binding buffer (˜1 ml for every 5 plates: 10 mM NaCl,20 mM HEPES, 0.22 mM KH₂PO₄, 1.26 mM CaCl₂, 0.81 mM MgSO₄, pH 7.4).Protein concentration was measured by the Bradford method (Bradford,1976) using Bio-Rad Reagent, with bovine serum albumin as a standard.Membranes were held on ice for up to one hour and used fresh, orflash-frozen and stored in liquid nitrogen.

Membranes were prepared similarly from 293, LM(tk-), and NIH-3T3 cells.To prepare membranes from baculovirus infected cells, 2×10⁷ Sf21 cellswere grown in 150 mm tissue culture dishes and infected with ahigh-titer stock of hY5BB3. Cells were incubated for 2-4 days at 27° C.,no CO₂ before harvesting and membrane preparation as described above.

Membranes were prepared similarly from dissected rat hypothalamus.Frozen hypothalami were homogenized for 20 seconds in ice-coldsonication buffer with the narrow probe of a Virtishear homogenizer at1000 rpm (Virtis, Gardiner, N.Y.). Large particles and debris werecleared by centrifugation (200×g, 5 min, 4° C.) and the supernatantfraction was reserved on ice. Membranes were further extracted from thepellet by repeating the homogenization and centrifugation procedure twomore times. The supernatant fractions were pooled and subjected to highspeed centrifugation (100,000×g, 20 min. 4° C.). The final membranepellet was resuspended by gentle homogenization into a small volume ofice-cold binding buffer (1 mL/ gram wet weight tissue) and held on icefor up to one hour, or flash-frozen and stored in liquid nitrogen.

Radioligand Binding to Membrane Suspensions

Membrane suspensions were diluted in binding buffer supplemented with0.1% bovine serum albumin to yield an optimal membrane proteinconcentration so that ¹²⁵I-PYY (or alternative radioligand such as¹²⁵I-NPY, ¹²⁵I-PYY_(3.36), or ¹²⁵I [Leu³¹Pro³⁴]PYY) bound by membranesin the assay was less than 10% of ¹²⁵I-PYY (or alternative radioligand)delivered to the sample (100,000 dpm/sample=0.08 nM for competitionbinding assays). ¹²⁵I-PYY (or alternative radioligand) and peptidecompetitors were also diluted to desired concentrations in supplementedbinding buffer. Individual samples were then prepared in 96-wellpolypropylene microtiter plates by mixing ¹²⁵I-PYY (25 μL) (oralternative radioligand), competing peptides or supplemented bindingbuffer (25 μL), and finally, membrane suspensions (200 μl). Samples wereincubated in a 30° C. water bath with constant shaking for 120 min.Incubations were terminated by filtration over Whatman GF/C filters(pre-coated with 1% polyethyleneimine and air-dried before use),followed by washing with 5 mL of ice-cold binding buffer. Filter-trappedmembranes were impregnated with MultiLex solid scintillant (Wallac,Turku, Finland) and counted for ¹²⁵I in a Wallac Beta-Plate Reader.Non-specific binding was defined by 300 nM human NPY for all receptorsexcept the Y4 subtypes; 100 nM human PP was used for the human Y4 and100 nM rat PP for the rat Y4. Specific binding in time course andcompetition studies was typically 80%; most non-specific binding wasassociated with the filter. Binding data were analyzed using nonlinearregression and statistical techniques available in the GraphPAD Prismpackage (San Diego, Calif.).

Functional Assay: Radioimmunoassay of cAMP

Stably transfected cells were seeded into 96-well microtiter plates andcultured until confluent. To reduce the potential for receptordesensitization, the serum component of the media was reduced to 1.5%for 4 to 16 hours before the assay. Cells were washed in Hank's bufferedsaline, or HBS (150 mM NaCl, 20 mM HEPES, 1 mM CaCl₂, 5 mM KCl, 1 mMMgCl₂, and 10 mM glucose) supplemented with 0.1 bovine serum albuminplus 5 mM theophylline and pre-equilibrated in the same solution for 20min at 37° C. in 5% CO₂. Cells were then incubated 5 min with 10 μMforskolin and various concentrations of receptor-selective ligands. Theassay was terminated by the removal of HBS and acidification of thecells with 100 mM HCl. Intracellular cAMP was extracted and quantifiedwith a modified version of a magnetic bead-based radioimmunoassay(Advanced Magnetics, Cambridge, Mass.). The final antigen/antibodycomplex was separated from free ¹²⁵I-cAMP by vacuum filtration through aPVDF filter in a microtiter plate (Millipore, Bedford, Mass.). Filterswere punched and counted for ¹²⁵I in a Packard gamma counter. Bindingdata were analyzed using nonlinear regression and statistical techniquesavailable in the GraphPAD Prism package (San Diego, Calif.).

Functional Assay: Intracellular calcium mobilization

The intracellular free calcium concentration was measured bymicrospectroflourometry using the fluorescent indicator dye Fura-2/AM(ref)- Stably transfected cells were seeded onto a 35 mm culture dishcontaining a glass coverslip insert. Cells were washed with HBS andloaded with 100 μl of Fura-2/AM (10 μM) for 20 to 40 min. After washingwith HBS to remove the Fura-2/AM solution, cells were equilibrated inHBS for 10 to 20 min. Cells were then visualized under the 40× objectiveof a Leitz Fluovert FS microscope and fluorescence emission wasdetermined at 510 nM with excitation wave lengths alternating between340 nM and 380 nM. Raw fluorescence data were converted to calciumconcentrations using standard calcium concentration curves and softwareanalysis techniques.

In vivo STUDIES IN RATS

Food intake in satiated rats

For these determinations food intake maybe measured in normal satiatedrats after intracerebroventricular application (i.c.v.) of NPY in thepresence or absence of the test compound. Male Sprague Dawley ratsciba-Geigy AG, Sisseln, Switzerland weighing between 180 g and 220 g areused for all experiments. The rats are individually housed in stainlesssteel cages and maintained on an 11:13 h light-dark cycle (lights off at18:00 h) at a controlled temperature of 21-23° C. at all times. Waterand food (NAFAG lab chow pellets, NAFAG, Gossau, Switzerland) areavailable ad libidum.

Rats under pentobarbital anesthesia are stereotaxically implanted with astainless steel guide cannula targeted at the right lateral ventricle.Stereotaxic coordinates, with the incisor bar set −2.0 mm belowinteraural line, are: −0.8 mm anterior and +1.3 mm lateral to bregma.The guide cannula is placed on the dura. Injection cannulas extend theguide cannulas −3.8 mm ventrally to the skull surface. Animals areallowed at least 4 days of recovery postoperatively before being used inthe experiments. Cannula placement is checked postoperatively by testingall rats for their drinking response to a 50 ng intracerebroventricular(i.c.v.) injection of angiotensin II. Only rats which drink at least 2.5ml of water within 30 min. after angiotensin II injection are used inthe feeding studies.

All injections are made in the morning 2 hours after light onset.Peptides are injected in artificial cerebrospinal fluid (ACSF) in avolume of 5 μl. ACSF contains: NaCl 124 mM, KCl 3.75 mM, CaCl₂ 2.5 mM,MgSO₄ 2.0 mM, KH₂PO₄ 0.22 mM, NaHCO₃ 26 mM and glucose 10 mM.porcine-NPY is dissolved in artificial cerebrospinal fluid (ACS). Fori.c.v. injection the test compounds are preferably dissolved inDMSO/water (10%, v/v). The vehicle used for intraperitoneal (i.p.) ,subcutaneous (s.c.) or oral (p.o.) delivery of compounds is preferablywater, physiological saline or DMSO/water (10% v/v), or cremophor/water(20% v/v), respectively.

Animals which are treated with both test compounds and p-NPY are treatedfirst with the test compound. Then, 10 min. after i.c.v. application ofthe test compound or vehicle (control), or 30-60 min after i.p., s.c.and p.o. application of the test compound or vehicle, 300 pmol of NPY isadministered by intracerebroventricular (i.c.v.) application.

Food intake may be measured by placing preweighed pellets into the cagesat the time of NPY injection. Pellets are removed from the cagesubsequently at each selected time point and replaced with a new set ofpreweighed pellets. The food intake of animals treated with testcompound may be calculated as a percentage of the food intake of controlanimals, i.e., animals treated with vehicle. Alternatively, food intakefor a group of animals subjected to the same experimental condition maybe expressed as the mean ±S.E.M. Statistical analysis is performed byanalysis of variance using the Student-Newman-Keuls test.

Food intake in food-deprived rats

Food-deprivation experiments are conducted with male Sprague-Dawley ratsweighing between 220 and 250 g. After receipt, the animals areindividually housed for the duration of the study and allowed freeaccess to normal food together with tap water. The animals aremaintained in a room with a 12 h light/dark cycle (8:00 a.m. to 8:00p.m. light) at 24° C. and monitored humidity. After placement intoindividual cages the rats undergo a 4 day equilibration period, duringwhich they are habituated to their new environment and to eating apowdered or pellet diet (NAFAG, Gossau, Switzerland).

At the end of the equilibration period, food is removed from the animalsfor 24 hours starting at 8:00 a.m. At the end of the fasting periodcompound or vehicle may be administered to the animals orally or byinjection intraperitoneally or intravenously. After 10-60 min. food isreturned to the animals and their food intake monitored at various timeperiods during the following 24 hour period. The food intake of animalstreated with test compound may be calculated as a percentage of the foodintake of control animals (i.e., animals treated with vehicle).Alternatively, food intake for a group of animals subjected to the sameexperimental conditions may be expressed as the mean ±S.E.M.

Food intake in obese Zucker rats

The antiobesity efficacy of the compounds according to the presentinvention might also be manifested in Zucker obese rats, which are knownin the as an animal model of obesity. These studies are conducted withmale Zucker fatty rats (fa/fa Harlan CPB, Austerlitz NL) weighingbetween 480 g and 500 g. Animals are individually housed in metabolismcages for the duration of the study and allowed free access to normalpowdered food and water. The animals are maintained in a room with a 12h light/dark cycle (light from 8:00 A.M. to 8:00 P.M.) at 24° C. andmonitored humidity. After placement into the metabolism cages the ratsundergo a 6 day equilibration period, during which they are habituatedto their new environment and to eating a powdered diet. At the end ofthe equilibration period, food intake during the light and dark phasesis determined. After a 3 day control period, the animals are treatedwith test compounds or vehicle (preferablywater or physiological salineor DMSO/water (10%,v/v) or cremophor/water (20%,v/v). Food intake isthen monitored over the following 3 day period to determine the effectof administration of test compound or vehicle alone. As in the studiesdescribed hereinabove, food intake in the presence of drug may beexpressed as a percentage of the food intake of animals treated withvehicle.

Materials

Cell culture media and supplements were from Specialty Media(Lavallette, N.J.). Cell culture plates (150 mm and 96-well microtiter)were from Corning (Corning, N.Y.). Sf9, Sf21, and High Five insectcells, as well as the baculovirus transfer plasmid, pBlueBacIII™, werepurchased from Invitrogen (San Diego, Calif.). TMN-FH insect mediumcomplemented with 10% fetal calf serum, and the baculovirus DNA,BaculoGold™, was obtained from Pharmingen (San Diego, Calif.). Ex-Cell400™ medium with L-Glutamine was purchased from JRH Scientific.Polypropylene 96-well microtiter plates were from Co-star (Cambridge,Mass.). All radioligands were from New England Nuclear (Boston, Mass.).Commercially available NPY and related peptide analogs were either fromBachem California (Torrance, Calif.) or Peninsula (Belmont, Calif.);[D-Trp³²]NPY and PP C-terminal fragments were synthesized by customorder from Chiron Mimotopes Peptide Systems (San Diego, Calif.). Bio-RadReagent was from Bio-Rad (Hercules, Calif.). Bovine serum albumin(ultra-fat free, A-7511) was from Sigma (St. Louis. Mo.). All othermaterials were reagent grade.

EXPERIMENTAL RESULTS

Applicants have synthesized and evaluated the binding and functionalproperties of several compounds at the cloned human Y1, human Y2, humanY4, and human Y5 receptors. As shown below in Table 5, applicants havediscovered several compounds which not only bind selectively to thehuman Y5 receptor but also act as Y5 receptor antagonists, as measuredby their ability to block NPY-induced inhibition of cAMP accumulation inforskolin-stimulated LM(tk-) cells stably transfected with the clonedhuman Y5 receptor.

Table 5: Evaluation of human Y5 receptor antagonists

The ability of the compounds to antagonize the Y-type receptors isreported as the K_(b). The K_(b) is derived from the EC₅₀, orconcentration of half-maximal effect, in the presence (EC₅₀) or absence(EC₅₀′) of compound, according to the equation:K_(b)=[NPY]/((EC₅₀/EC₅₀′)−1). Results shown are representative of atleast three indepenent experiments.

N.D.=Not determined.

TABLE 5 Binding Affinity (K_(i) (nM) vs. ¹²⁵I-PYY) Example HumanReceptor K_(b) (nM) — Y1 Y2 Y4 Y5 — 31 5550 1000 8020 14 6.0 32 3550 95511700 11 23 36 16000 7760 20400 8.3 26 38 13000 1610 18500 9.8 16 4017200 7570 27500 11 3.0 37 14500 617 21500 26 38 77 3240 851 13100 17311 44 23700 58200 19300 14 50 45 48700 5280 63100 28 49

Several of the compounds were further tested using in vivo animal modelsof feeding behavior. Since NPY is the strongest known stimulant offeeding behavior, experiments were performed with several compounds toevaluate the effect of the compounds described above on NPY-inducedfeeding behavior in satiated rats.

First, 300 pmole of porcine NPY in vehicle (A.C.S.F.) was administeredby intracerebroventricular (i.c.v.) injection, along with i.p.administration of compound vehicle (10% DMSO/water), and the food intakeof NPY-stimulated animals was compared to food intake in animals treatedwith the vehicles. The 300 pmole injection of NPY was found tosignificantly induce food intake (p<0.05; Student-Newman-Keuls).

Using the 300 pmole dose of NPY found to be effective to stimulatefeeding, other animals were treated with the compounds byintraperitoneal (i.p.) administration, followed 30-60 minutes later byi.c.v. NPY administration, and measurement of subsequent food intake. Asshown in Table 6, NPY-induced food intake was significantly reduced inanimals first treated with the compounds (p<0.05; Student-Newman-Keuls).These experiments demonstrate that NPY-induced food intake issignificantly reduced by administration to animals of a compound whichis a Y5-selective antagonist.

Table 6. NPY-induced cumulative food intake in rats treated with eitherthe i.c.v. and i.p. vehicles (control), 300 pmole NPY alone (NPY), or inrats treated first with compound and then NPY (NPY+compound). Foodintake was measured 4 hours after stimulation with NPY. Food intake isreported as the mean ±S.E.M. intake for a group of animals.

TABLE 6 Example 31 32 Compound Dose 10 30 (mg/kg i.p.) control 2.4 ± 0.72.9 ± 0.8 (vehicles only) NPY 5.8 ± 0.5 4.9 ± 0.4 NPY + 3.8 ± 0.4 1.5 ±0.6 compound

Since food deprivation induces an increase in the hypothalamic NPYlevels, it has been postulated that food intake following a period offood deprivation is NPY-mediated. Therefore, the Y5 antagonists of Table5 were administered co conscious rats following a 24 h food deprivation.Each of the human Y5 receptor antagonists shown in Table 5 was able tosignificantly reduce NPY-induced food intake in the animals, as shownbelow in Table 7. The food intake intake of animals treated with testcompound is reported as a percentage of the food intake measured forcontrol animals (treated with vehicle), i.e., 25% means the animalstreated with the compound consumed only 25% as much food as the controlanimals. Measurements were performed two hours after administration ofthe test compound.

TABLE 7 Two-hour food intake of NPY-stimulated rats. Food intake isexpressed as the percentage of intake compared to control rats. MeanExample (%) 31 27 32 36 36 35 38 80 40 55 37 58 77 32 44 73 45 84

These experiments indicate that the compounds of the present inventioninhibit food intake in rats, especially when administered in a range ofabout 0.01 to about 100 mg/kg rat, by either oral, intraperitoneal orintravenous administration. The animals appeared normal during theseexperiments, and no ill effects on the animals were observed after thetermination of the feeding experiments.

The binding properties of the compounds were also evaluated with respectto other cloned human G-protein coupled receptors. As shown in Table 8,below, the Y5-selective compounds described hereinabove exhibited loweraffinity for receptors other than the Y-type receptors.

TABLE 8 Cross-reactivity of compounds at other cloned human receptorsCom- Receptor (pKi) pound α_(1d) α_(1b) α_(1a) α_(2a) α_(2b) α_(2c) H1H2 D3 5HT_(1a) 5HT₂ 5HT₇ 5HT_(1F) 5HT_(1E) 5HT_(1Dβ) 5HT_(1Dα) 31 6.687.17 7.08 6.52 6.51 7.07 6.33 5.92 6.61 5.88 6.74 6.50 5.30 5.30 5.305.32 32 6.90 7.35 7.47 6.74 6.58 7.07 7.04 6.29 6.69 5.54 6.55 6.42 5.305.30 5.30 6.04 36 7.01 7.22 7.72 7.31 6.96 7.39 6.73 5.85 6.35 6.73 5.936.37 5.30 5.30 5.37 5.94 38 N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D.N.D. N.D. N.D. N.D. N.D. N.D. N.D. 40 6.80 6.98 7.34 7.05 6.43 7.15 6.225.72 6.29 6.56 5.99 6.39 5.30 5.30 5.41 5.98 37 N.D. N.D. N.D. N.D. N.D.N.D. N.D. N.D N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. 77 6.66 6.67 7.076.21 5.95 6.79 6.43 6.43 5.93 5.82 5.99 5.35 5.30 5.30 5.39 5.62 44 N.D.N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D.N.D. 45 N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D.N.D. N.D. N.D.

EXPERIMENTAL DISCUSSION

Y5 receptors are highly attractive targets for appetite and weightcontrol based on several lines of research (Sahu and Kalra, 1993). NPYis the most potent stimulant of feeding behavior yet described (Clark etal., 1984; Levine and Morley, 1984; Stanley and Leibowitz, 1984). Directinjection of NPY into the hypothalamus of rats can increase food intake−10-fold over a 4-hour period (Stanley et al., 1992). NPY-stimulatedrats display a preference for carbohydrates over protein and fat(Stanley et al., 1985). Interestingly, NPY and NPY mRNA are increased infood-deprived rats (Brady et al., 1990; O'Shea and Gundlach, 1991) andalso in rats which are genetically obese (Sanacora et al., 1990) or madediabetic by treatment with streptozotocin (White et al., 1990). Onepotential explanation is that NPY, a potent stimulant of feedingbehavior in normal rats, is disregulated in the overweight or diabeticanimal so that food intake is increased, accompanied by obesity. Thephysiological stress of obesity increases the risk for health problemssuch as cardiovascular malfunction, osteoarthritis, andhyperinsulinemia, together with a worsened prognosis for adult-onsetdiabetes. A nonpeptide antagonist targeted to the Y5 receptor couldtherefore be effective as a way to control not only appetite and bodyweight but an entire range of obesity- and diabetes-related disorders(Dryden et al., 1994). There is also neurochemical evidence to suggestthat NPY-mediated functions are disregulated in eating disorders such asbulimia and anorexia nervosa, so that they too could be responsive totreatment by a Y5-selective drug. It has been proposed, for example,that food intake in NPY-stimulated rats mimics the massive foodconsumption associated with binge eating in bulimia (Stanley, 1993). CSFlevels of PYY but not NPY were elevated in bulimic patients whoabstained from binging, and then diminished when binging was allowed(Berrettini et al., 1988). Conversely, NPY levels were elevated inunderweight anorectic patients and then diminished as body weight wasnormalized (Kaye et al., 1990).

As described above, the human and rat in vitro expression models wereused in combination to screen for compounds intended to modulateNPY-dependent feeding behavior. Using this approach, applicants havediscovered several compounds which inhibit feeding behavior in animalmodels, which should lead to additional drug discoveries. The compoundsaccording to the present invention inhibit food intake in Zucker obeserats in a range especially of about 0.01 to about 100 mg/kg after oral,intraperitoneal or intravenous administration.

The Y5 pharmacological profile further offers a new standard by which toreview the molecular basis of all NPY-dependent processes. Such anexercise suggests that the Y5 receptor is likely to have a physiologicalsignificance beyond feeding behavior. It has been reported, for example,that a Y-type receptor can regulate luteinizing hormone releasinghormone (LHRH) release from the median eminence of steroid-primed ratsin vitro with an atypical Y1 pharmacological profile. NPY, NPY₂₋₃₆, andLP-NPY were all effective at 1 uM but deletion of as few as four aminoacids from the N-terminus of NPY destroyed biological activity. The Y5may therefore represent a therapeutic target for sexual or reproductivedisorders. It is worth while considering that the Y5 is so similar inpharmacological profile to the other Y-type receptors that it may havebeen overlooked among a mixed population of Y1, Y2 and Y4 receptors.Certain functions now associated with these subtypes could therefore bereassigned to Y5 as our pharmacological tools grow more sophisticated.By offering new insight into NPY receptor pharmacology, the Y5 therebyprovides a greater clarity and focus in the field of drug design.

TABLE 9 Pathophysiological Conditions Associated With NPY The followingpathological conditions have been linked to either 1) application ofexogenous NPY, or 2) changes in levels of endogenous NPY. 1 obesity Sahuand Kalra, 1993 2 eating disorders Stanley, 1993 (anorexia and bulimianervosa) 3 sexual/reproductive Clark, 1994 function 4 depression Heiligand Weiderlov, 1990 5 anxiety Wahlestedt et al., 1993 6 cocaineWahlestedt et al., 1991 addiction 7 gastric ulcer Penner et al., 1993 8memory loss Morley and Flood, 1990 9 pain Hua et al., 1991 10 epilepticseizure Rizzi et al., 1993 11 hypertension Zukowska-Grojec et al., 199312 subarachnoid Abel et al., 1988 hemorrhage 13 shock Hauser et al.,1993 14 circadian rhythm Albers and Ferris, 1984 15 nasal congestionLacroix et al., 1988 16 diarrhea Cox and Cuthbert, 1990 17 neurogenicZoubek et al., 1993 voiding dysfunction

A successful strategy for the design of a Y5-receptor based drug or forany drug targeted to single G protein-coupled receptor subtype involvesthe screening of candidate compounds 1) in radioligand binding assays soas to detect affinity for cross-reactive G protein-coupled receptors,and 2) in physiological assays so as to detect undesirable side effects.In the specific process of screening for a Y5-selective drug, thereceptor subtypes most likely to cross-react and therefore mostimportant for radioligand binding screens include the other “Y-type”receptors, Y1, Y2, Y3, and Y4. Cross-reactivity between the Y5 and anyof the other subtypes could result in potential complications assuggested by the pathophysiological indications listed in Table 9. Indesigning a Y5 antagonist for obesity and appetite control, for example,it is important not to design a Y1 antagonist resulting in hypertensionor increased anxiety, a Y2 antagonist resulting in memory loss, or a Y4antagonist resulting in increased appetite.

TABLE 10 Y-Type Receptor Indications Y-type Receptor Receptor DrugIndications Subtype Activity Reference obesity, a typical Y1 antagonistSahu and appetite Kalra, disorder 1993 adult onset a typical Y1antagonist Sahu and diabetes Kalra, 1993 bulimia a typical Y1 antagonistStanley, nervosa 1993 pheochromocy- Y1 antagonist Grouzman toma- et al.,induced 1989 hypertension subarachnoid Y1 antagonist Abel et hemorrhageal., 1988 neurogenic Y1 antagonist Zukowska- vascular Y2 antagonistGrojec et hypertrophy al., 1993 epileptic Y2 antagonist Rizzi et seizureal., 1993 hypertension peripheral Y1 antagonist Grundemar central,central Y3 agonist and peripheral central Y2 antagonist Hakanson,regulation 1993 Barraco et al., 1991 obesity, Y4 or PP agonist Malaisse-appetite Lagae et disorder al., 1977 anorexia a typical Y1 agonistBerrettini nervosa et al., 1988 anxiety Y1 agonist Wahlestedt et al.,1993 cocaine Y1 agonist Wahlestedt addiction et al., 1991 stress- Y1agonist Penner et induced Y4 or PP agonist al., 1993 gastric ulcermemory loss Y2 agonist Morley and Flood, 1990 pain Y2 agonist Hua etal., 1991 shock Y1 agonist Hauser et al., 1993 sleep Y2 not clear Albersdisturbances, and jet lag Ferris, 1984 nasal Y1 agonist Lacroixdecongestion Y2 agonist et al., 1988 diarrhea Y2 agonist Cox andCuthbert, 1990

The Y5 receptor represents an enormous opportunity for the developmentof novel and selective drug therapies, particularly those targeted toappetite and weight control, but also for memory loss, depression,anxiety, gastric ulcer, epileptic seizure, pain, hypertension,subarachnoid hemorrhage, sleeping disturbances, nasal congestion,neurogenic voiding dysfuncion, and diarrhea.

In particular, the discovery of Y5-slective antagonists which inhibitfood intake in rats provides a method of modifying feeding behavior in awide variety of vertebrate animals.

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What is claimed is:
 1. A compound having the structure:

wherein Ar is

wherein p is an integer from 0 to 2; wherein X is a single bond; whereineach R₂ is independently H; F; Cl; Br; I; NO₂; OH; C₁-C₄ alkyl; C₂-C₄alkenyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; SO₂N(R₅)₂; phenoxy;phenyl; or naphthyl; and wherein the phenoxy, phenyl, or naphthyl issubstituted with H, F, Cl, Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, or NO₂; wherein each R₃ is independently H; F; Cl; Br; I;NO₂; OH; C₁-C₄ alkyl; C₂-C₄ alkenyl; C₁-C₄ aIkoxy; C₁-C₄ hydroxyalkyl;C₁-C₄ methoxyalkyl; C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂;NHCOR₅; N(COR₅)₂; NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅;CON(R₅)₂; or SO₂N(R₅)₂; or R₂ and R₃ present on adjacent carbon atomscan constitute C₅-C₇ cycloalkyl; wherein each R₄ is independently H; F;Cl; Br; I; NO₂; OH; C₁-C₄ alkyl; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄methoxyalkyl; C₁-C₄ monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅;N (COR₅)₂; NHCO₂R₅; NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; orSO₂N(R₅)₂; wherein each R₅ is independently H; C₁-C₃ alkyl; C₁-C₃monohaloalkyl; or C₁-C₃ polyhaloalkyl; wherein L′ is —NR₁—L—; wherein Lis

wherein R₁ is H; or C₁-C₃ straight chained alkyl; wherein one dashedline is a double bond and the other dashed line is a single bond;wherein each R6 is independently H; CN; OR₅; C₁-C₅ alkyl; CH₂OR₅;CON(R₅)₂; CO₂R₅; phenyl; or naphthyl; wherein the phenyl, or naphthyl issubstituted with H, F, Cl, Br, I, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, or NO₂; wherein i is an integer from 1 to 4; wherein n is aninteger from 0 to 3; wherein m is an integer from 0 to 3; wherein K is—CH₂—NR₁₀—CHR₇—(CH₂)₁—; wherein j is an integer from 0 to 3; wherein R₇is H; C₁-C₆ alkyl; CH₂OR₅; (CH₂)_(p)NHCO₂R₅; (CH₂)_(p)NHSO₂R₅;CH₂N(R₁₁)₂; phenyl; or naphthyl; wherein W is

wherein R₈ is independently H; F; Cl; Br; I; NO₂; OH; ═O; C₁-C₄ alkyl;C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ methoxyalkyl; C₁-C₄monohaloalkyl; C₁-C₄ polyhaloalkyl; N(R₅)₂; NHCOR₅; N(COR₅)₂; NHCO₂R₅;NHCONHR₅; NHSO₂R₅; N(SO₂R₅)₂; CO₂R₅; CON(R₅)₂; or SO₂N(R₅)₂; wherein R₁₀is H; or C₁-C₆ alkyl; wherein R₁₁ is H; COR₅; COR₅; SO₂R₅; or SO₂R₁₂;and wherein R₁₂ is phenoxy; phenyl, or naphthyl; wherein the phenoxy,phenyl, or naphthyl is substituted with H, F, Cl, Br, I, CF₃, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, NO₂, or phenyl; or apharmaceutically acceptable salt thereof.
 2. An (+) enantiomer of thecompound of claim
 1. 3. An (−) enantiomer of the compound of claim
 1. 4.A compound of claim 1, wherein R₁ is H; wherein L is

and wherein W is


5. A compound of claim 4, wherein Ar is:

wherein each of R₂, R₃ and R₄ is independently H; F, Cl, Br or I; NO₂;OH; C₁-C₄ alkoxy; C₁-C₄ hydroxyalkyl; C₁-C₄ monohaloalkyl; C₁-C₄polyhaloalkyl; or N(R₅)₂; wherein each R₅ is independently C₁-C₃ alkyl;wherein L is

wherein R₇ is H; CH₂OH; or CH₂OR₅; and wherein W is


6. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


7. A method of modifying feeding behavior of a subject in need thereofwhich comprises administering to the subject an effective amount of thecompound of claim 1 to decrease the consumption of food by the subjectso as to thereby modify the feeding behavior of the subject.
 8. A methodof treating a feeding disorder in a subject in need thereof whichcomprises administering to the subject an effective amount of thecompound of claim 1 to decrease the consumption of food by the subject.9. The method of claim 7 or 8, wherein the feeding disorder is bulimia,obesity or bulimia nervosa.
 10. The method of claim 9, wherein thesubject is a vertebrate, a mammal, a human or a canine.
 11. The methodof claim 7 or 8, wherein the compound is administered in combinationwith food.